|Year : 2017 | Volume
| Issue : 2 | Page : 57-68
Cardioprotective effects of angiotensin converting Enzyme II
Leta Melaku1, Andualem Mossie2
1 Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Ethiopia
2 Department of Biomedical Sciences, College of Public Health and Medical Sciences, Jimma University, Jimma, Oromia, Ethiopia
|Date of Submission||23-Feb-2017|
|Date of Decision||23-Jun-2017|
|Date of Acceptance||30-Jun-2017|
|Date of Web Publication||17-Jul-2017|
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Arsi
Source of Support: None, Conflict of Interest: None
To circumvent the major threats of low blood volume and low blood pressure, animals need powerful mechanisms for salt and water conservation, which is renin–angiotensin system (RAS). Activation of RAS is therefore a useful response in many demanding situations. However, an increased activity of the RAS, especially in combination with other cardiovascular risk factors, may lead to a cascade of deleterious effects such as hypertension, atherosclerosis, myocardial remodeling, heart failure, ischemic stroke, and diabetes mellitus. Many of these pathophysiological actions of angiotensin II (Ang II) may still be viewed as being homeostatic in principle but harmful if carried to excess. Numerous experimental studies have indicated that angiotensin-converting enzyme II (ACE II) efficiently hydrolyzes the potent vasoconstrictor Ang II to Ang 1–7. Thus, the axis formed by ACE II/Ang 1–7/Mas appears to represent an endogenous counter-regulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and Ang II Type 1 receptor (AT1R). Although most of the well-known cardiovascular and renal effects of RAS are attributed to ACE, an important enzyme in the generation of Ang II, much less is known about the functions of ACE II. This review summarizes recently published data on the basic properties of ACE II and Ang 1–7 and a summary of the evidence from experimental and clinical studies of various pathological conditions related to the biological roles of ACE II/Ang 1–7/Mas in the heart.
Keywords: Angiotensin 1–7, angiotensin-converting enzyme II, heart, Mas receptor, renin–angiotensin system
|How to cite this article:|
Melaku L, Mossie A. Cardioprotective effects of angiotensin converting Enzyme II. Int J Clin Exp Physiol 2017;4:57-68
|How to cite this URL:|
Melaku L, Mossie A. Cardioprotective effects of angiotensin converting Enzyme II. Int J Clin Exp Physiol [serial online] 2017 [cited 2017 Nov 21];4:57-68. Available from: http://www.ijcep.org/text.asp?2017/4/2/57/210928
| Introduction|| |
To circumvent the major threats of low blood volume and low blood pressure, animals and our ancestors, with a diet relatively poor in sodium, needed powerful mechanisms for salt and water conservation, and these organisms relied heavily on one of the oldest hormone systems called renin–angiotensin system (RAS). In 2000, angiotensin-converting enzyme (ACE) II was serendipitously discovered by two independent research groups who had conducted a study upon characterization of cDNA genomic-based strategies., ACE II (ACE-related carboxypeptidase or angiotensin-converting enzyme homolog) is a mono-carboxypeptidase Type I transmembrane protein that contains 805 amino acids and it has an extracellular (ecto) domain (amino acids 18–739), a transmembrane region (amino acids 740–768), and an intracellular tail. The extracellular part of ACE II [Figure 1] contains the catalytic domain (amino acids 147–555), which has a substrate-binding region (amino acids 273–345) and a typical HEMGH metalloproteinase zinc-binding site (amino acids 374–378).,,, The catalytic domain of ACE II is 42% identical to that of ACE. The peptidase activity of ACE II depends on the C-terminus sequence of the substrate (sequence specificity). The C-terminal part of ACE II (614–805) is homologous (48% identity) to a transporter protein known as collectrin., ACE II substrates generally have a hydrophobic or basic residue at the C-terminal end, preceded by a Pro-X-Pro motif, where either one of the two proline residues is sufficient to allow ACE II-dependent hydrolysis. In this circumstance, ACE II displays potent peptidase activity to angiotensin II (Ang II) (Pro-Phe), Ang I (Pro-Phe-His-Leu), and des-Arg 9-bradykinin (BK) (Ser-Pro-Phe) but shows no activity toward Ang 1–9, Ang 1–7, or BK  [Figure 2]. ACE II can also hydrolyze other bioactive peptides, such as apelin-13, β-casomorphin, dynorphin A 1–13, and ghrelin. Within the RAS, ACE II competes with ACE because it is capable of hydrolyzing the inactive decapeptide Ang I into the nonapeptide Ang 1–9, thus decreasing the amount of Ang I available for pressor Ang II generation by ACE. To the same extent, ACE II degrades the vasoconstrictor Ang II into Ang 1–7, which is the most important active product., The Ang 1–7 can be primarily generated through two routes. First, both ACE II and prolyl carboxypeptidase can directly hydrolyze Ang II to yield Ang 1–7; second, this mono-carboxypeptidase can also remove the amino acid leucine from the C-terminus of Ang I to form the biologically active peptide Ang 1–9,, which is then cleaved by either neutral endopeptidase (NEP) or ACE to yield Ang 1–7,, [Figure 2]. The heart, brain, and kidney are major sources of Ang 1–7 production.
|Figure 1: Structure of the extracellular domain (from Ser19 to Asp615) of human ACE II. In this image, the extracellular domain is arbitrarily divided into two subdomains (shown in green and purple), forming a deep cleft that is proposed to be the active site for substrate binding and catalysis. The catalytic domain (amino acids 147–555) has a substrate-binding region (amino acids 273–345) and a typical HEMGH metalloproteinase zinc-binding site (amino acids 374–378). The regions shown in ball-and-stick figuration are proposed binding sites for the angiotensin-converting enzyme II inhibitor MLN-4760|
Click here to view
|Figure 2: Overview of the angiotensin-converting enzyme II–angiotensin 1–7 pathway. Angiotensin-converting enzyme II and prolyl carboxypeptidase converts angiotensin II to angiotensin 1–7. Angiotensin-converting enzyme II can also convert angiotensin I to angiotensin 1–9, which is then cleaved by either neutral endopeptidase or angiotensin-converting enzyme to yield angiotensin 1–7. The membrane-bound angiotensin-converting enzyme II can be cleaved by the metalloproteinase ADAM 17, forming a soluble form of angiotensin-converting enzyme II. The physiological relevance of soluble angiotensin-converting enzyme II is not fully understood|
Click here to view
In the human coronary circulation, NEP seems to have a more prominent role in Ang 1–7 production than ACE II. Pharmacokinetic experiments have determined that, in humans, Ang 1–7 has a short half-life of ~0.5 h. Following subcutaneous injection, the peptide is quickly available in the blood and reaches its peak plasma concentration at ~1 h. In rats, the plasma half-life of Ang 1–7 is only 9 s. It has been established that Ang 1–7 binds to a non-AT1R/AT2R originally identified as the Mas oncogene receptor  and mediates vasodilatation; myocardial protection; antiarrhythmic at low concentration, antihypertensive, and positive inotropic effects; and inhibition of pathological cardiac remodeling within the cardiovascular system.,, In addition, it is thought to have favorable effects on metabolism by lessening insulin resistance.,, Although most effects are protective, some seem to be variable. Many of the diverse actions of Ang II, the major end-product of the RAS, can be viewed in a single conceptual framework as serving to prevent life-threatening shrinkage of intravascular volume (rapid actions of Ang, in combination with the sympathetic nervous system), to help maintain volume homeostasis by minimizing the changes in arterial pressure and fluid volumes required to achieve sodium balance (prevention of salt sensitivity), and to increase the efficiency of cardiovascular dynamics by promoting the growth of the heart and vessels and sensitizing blood vessels to vasoconstrictor agents (slowest actions of Ang) through its coordinated effects on the heart, blood vessels, kidneys, and nervous system., Activation of the RAS is therefore a useful response in many demanding situations. However, an increased activity of the RAS, especially in combination with other cardiovascular risks factors, may lead to a cascade of deleterious effects such as hypertension, atherosclerosis, myocardial remodeling, heart failure (HF), ischemic stroke, and diabetes mellitus., Many of these pathophysiological actions of Ang II may still be viewed as being homeostatic in principle but harmful if carried to excess. Thus, ACE II may have a role to counterbalance the action of ACE in producing the vasoconstrictor Ang II, leading to have protective effects in various tissues and to prevent overactive RAS-associated diseases, including hypertension.,,,, The affinity of ACE II to Ang II (Km= 2.0 μmol/l, which represents the concentration of substrate required for the enzyme to achieve half maximum catalytic velocity, that is, the higher the Km value, the lower the affinity) is higher than to Ang I (Km= 6.9 μmol/l). The ACE II catalytic efficiency for Ang II is >300 times that for Ang I.
A newly described RAS component, ACE II, has been characterized recently in humans , and in mice. In humans, ACE II was found at various levels in 72 tissues that also express ACE mRNA  and it is highly expressed in kidneys, blood vessels, heart, lung, brain, and testis.,,, Interestingly, it has also been reported to be localized in glucose-regulating tissues such as pancreas, including β-cells ,, adipose tissue, and liver.,
| Cardiac Actions of Ace Ii|| |
The components of local cardiac RAS
For a number of years, ACE and its main biologically active peptide Ang II have assumed a central position in the cardiac RAS. With the discovery of ACE II, a new regulator entered within the established metabolic RAS pathways. The presence and synthesis of RAS components in the heart suggest that locally produced bioactive Ang peptides modulate cardiac structure and function., Components of the local cardiac RAS are heterologously distributed on different cell types within the heart. For instance, angiotensinogen is primarily distributed in atrial muscle and the neuronal fibers of the conduction system, with small amounts in the subendocardial region of the ventricle. In contrast, ACE is primarily expressed by coronary endothelial cells and cardiac fibroblasts. In addition, ACE expression can be detected in all four heart valves, coronary blood vessels, aorta pulmonary arteries, endocardium, as well as epicardium., However, ACE II is localized to the endothelium and smooth muscle cells of most intramyocardial vessels, including capillaries, venules, and medium-sized coronary arteries and arterioles. Furthermore, ACE II protein expression was detected in cardiac myocytes from failing human hearts. Ang I is extensively metabolized during a single pass through the coronary bed leading to the generation of Ang II, Ang III, Ang IV, and Ang 1–7 in isolated hearts from normal , and diabetic rats. As a result of its affinity to Ang II is higher than to Ang I,, recent studies report that ACE II is an important regulator of cardiac pathophysiology., However, it should be stressed that the role of ACE II in heart function and structure might depend on the species. Interestingly, ACE II expression has been reported to be increased in failing human heart ventricle.,, Nevertheless, there are contrasting findings in rat hearts. While an increase of both ACE and ACE II was found by Burrell et al. in hearts from Sprague–Dawley rats after myocardial infarction (MI), Ishiyama et al. observed an increase in ACE II expression only after AT1 blockade in Lewis normotensive rats. These divergent results further suggest that ACE II effects are strain dependent. ACE II gene transfection using lentiviral vectors significantly attenuated cardiac damage in spontaneously hypertensive rat (SHR) and in Ang II-infused Sprague–Dawley rats. In addition, the stage of the disease apparently influences the expression of ACE II.
At the early phase of MI, ACE II activity in plasma and left ventricles is increased in rats while the plasma and left ventricular (LV) ACE II activities and mRNA levels are lower than in controls at 8 weeks postinfarction. Similar findings were observed regarding the cardiac expression of Mas, i.e., it changes depending on the nature and duration of the physiological and pathological stimuli. Ang 1–7, which is also one of the components of RAS, is present within hearts. The localization and local generation of Ang 1–7 have been demonstrated within aortic root, coronary sinus, and right atrium of dogs at basal conditions, and its levels were markedly reduced following treatment with the ACE inhibitor CGS-14831. In addition, immunohistochemical staining revealed that Ang 1–7 is expressed in rat cardiac myocytes  and sinoatrial node cells. Of note, the Ang 1–7, Ang 1–7 receptor, Mas, mRNA, and protein of Ang 1–7 are localized in human cardiac tissues.,, It is important to note that although all the components of RAS are present in the heart, not all of them are believed to be synthesized in heart. For example, the question whether renin is synthesized in heart or is derived primarily from circulation remains still unresolved.
The role of ACE II on conductivity of the heart
In several published studies, Ang II has been implicated in conduction abnormalities although some results appear contradictory. Slowed conduction was associated with increased myocardial and plasma ACE activity. Moreover, administration of an ACE inhibitor improved conduction velocities in cardiomyopathy using a Syrian Hamster model.,, These observations suggest that Ang II slows cardiac conduction. This conclusion is further supported by the findings of slowed ventricular conduction in mice overexpressing the AT1R. However, in contrast, in cardiac myocyte cultures, Ang II stimulated an increase in connexion 43, a protein implicated in the upregulation of cardiac conduction, implying that Ang II may accelerate cardiac conductance. Interestingly, in ACE II null mice, elevated levels of Ang II did not affect normal conductivity, and the mice appear to have a normal life span at least under nonstress laboratory conditions.
The question whether cardiac conduction is, in fact, influenced by the RAS under physiological condition was examined and it has been demonstrated that Ang 1–7, a main product of ACE II enzymatic activity in the heart, decreases the incidence and duration of ischemia–reperfusion arrhythmias in isolated perfused rat hearts  apparently involving activation of the sodium pump. These effects were abolished by ouabain. In addition, Ang 1–7 decreased total (Na +, K +, Mg 2+)-ATPase activity in sheep atrium. Furthermore, the antiarrhythmogenic effect of Ang 1–7 was blocked by Ang 1–7 antagonist A-779 and by cyclooxygenase inhibitor indomethacin. This peptide also improved postischemic contractile function in isolated heart preparations by a mechanism involving Mas and the release of BK and prostaglandins. However, at concentrations nearly 10,000-fold higher, Neves et al. found that Ang 1–7 facilitated reperfusion arrhythmias in isolated perfused rat hearts. In keeping with these latter data, transgenic mice overexpressing ACE II in the heart presented sudden death due to cardiac arrhythmias. These observations suggest that only very high local concentrations of Ang 1–7 exert deleterious effects in the heart possibly through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase  or release of norepinephrine. In fact, transgenic rats presenting a local increase of Ang 1–7 of up to 20-fold in the heart did not show any sign of arrhythmias.
The role of ACE II on contractility of the heart
Although hearts from young ACE II-mutant mice are functionally normal, hearts of old ACE II-deficient mice in this particular mouse background display a reduction in cardiac contractility as demonstrated by 40% reduction in fractional shortening and velocity of circumferential shortening (heart rate corrected) with slight ventricular dilation. The significance of ACE II in regulating cardiac function is further highlighted by the thinning of the LV wall in aged ACE II-mutant mice. This progressive cardiac dysfunction occurred without myocardial fibrosis or hypertrophy and in the absence of the myosin heavy chain isoform switches which is also typically found in other animal models of HF. Thus, one may speculate that the observed phenotype closely resembles the defective heart found in patients with cardiac stunning/hibernation. Cardiac stunning and hibernation reflect adaptive responses to prolonged tissue hypoxia that occurs in coronary artery disease or after bypass surgery.
In these human diseases and related animal models, chronic hypoxic conditions lead to compensatory changes in myocyte metabolism, upregulation of hypoxia-induced genes, and reduced heart function. Accordingly, the hearts of ACE II null mice show upregulation of mRNA expression of hypoxia-inducible genes such as BNIP362 and PAI-1. The magnitude of increased expression of these hypoxia-inducible genes resembles previously observed levels in other hypoxic models such as myocyte-specific vascular endothelial growth factor-mutant mice. However, the link between cardiac stunning/hibernation and the heart defect observed in ACE II-knockout (KO) mice has to be investigated further. Whether ACE II expression levels indeed change under conditions of hypoxia remains to be demonstrated. ACE II-KO mice show also increased local heart Ang II levels. Interestingly, both the cardiac phenotype and increased Ang II levels were completely reversed by additional deletion of ACE gene (i.e. ablation of ACE expression on an ACE II-mutant background abolished the cardiac dysfunction phenotype of ACE II single-KO mice). The heart function of ACE/ACE II double-mutant mice was similar to that in ACE single-mutant and wild-type littermates. The normal cardiac functions of ACE/ACE II double-mutant mice suggest that the catalytic products of ACE account for the observed contractile impairment of old ACE II single-mutant mice. These observations for the first time demonstrated at the genetic level that ACE II counterbalances the enzymatic actions of ACE. It seems that increased local cardiac Ang II might have been the cause for the cardiac abnormalities in ACE II-deficient mice. However, it remains unclear why, despite the elevated plasma and heart Ang II levels, the heart of the ACE II-deficient mice did not show any evidence for cardiac hypertrophy. In fact, it is well established that cardiac myocytes express Ang II receptors and undergo hypertrophy in response to Ang II. However, in vivo, elevated cardiac Ang II levels alone do not directly induce cardiac hypertrophy but do increase interstitial fibrosis. Thus, it is important to note that Ang II-independent pathways could also play an important role in ACE/ACE II-regulated heart function. Apparently, generation of Ang 1–7 directly from Ang II through the cleavage of the C-terminal amino acid phenylalanine by ACE II is physiologically and biochemically more relevant. According to Loot et al., chronic infusion (8 weeks) of Ang 1–7 improved coronary perfusion and preserved cardiac function in an experimental rat model of HF induced by ligation of the left coronary artery. The vascular endothelial dysfunction observed in aortic rings from rats with MI was also reversed by chronic infusion of Ang 1–7.
In addition, Ang 1–7 immunoreactivity was significantly increased in the tissue surrounding the infarct area of rat hearts with MI , published the first study, demonstrating that the compound AVE 0991 is a nonpeptide and orally active Ang 1–7 receptor agonist that mimics the Ang 1–7 effects in bovine endothelial cells. Pinheiro et al. and Lemos et al. reported that this compound acts as a Mas agonist in the kidney and isolated aortic rings, respectively. Another study also revealed that AVE 0991 preserved cardiac function and attenuated the development of hypertrophy and fibrosis in hearts from rats chronically treated with isoproterenol. This nonpeptide Ang 1–7 analog also significantly improved the cardiac function in hearts subjected to MI and preserved the myocardium after ischemia. Furthermore, long-term treatment with AVE 0991 prevented the end-organ damage in hearts from SHRs treated with N (G)-nitro-l-arginine methyl ester. Recently, it has been shown that the inclusion of Ang 1–7 into the cavity formed by the oligosaccharide hydroxypropyl β-cyclodextrin (HPβCD) could protect the peptide during the passage through the gastrointestinal tract. Taking advantage of this formulation, Marques et al., found that chronic oral administration of HPβCD/Ang 1–7 significantly attenuated the impairment of heart function and cardiac remodeling induced by isoproterenol treatment and MI in rats. The actions of Ang 1–7 in coronary vessels include biochemical and functional alterations leading to vasodilatation either directly in artery rings or indirectly through BK potentiation or by opposing Ang II actions. In isolated canine coronary artery rings precontracted with the thromboxane A2 analog, U46619, Ang 1–7 elicited a dose-dependent vasorelaxation, which was completely blocked by the nonselective Ang II antagonist (Sar 1, Thr 8)-Ang II, but not by the selective AT1 or AT2 antagonists, CV11974 and PD 123319, respectively. This heptapeptide induced a concentration-dependent dilator response in porcine coronary artery rings, which were markedly attenuated by nitric oxide (NO) inhibition. However, Gorelik et al. observed a vasodilator effect of Ang 1–7 only in BK-stimulated pig coronary artery rings. Furthermore, Ang 1–7 elicited an increase in the vasodilator effect of BK in isolated perfused rat hearts. This effect was dependent on Mas and NO and prostaglandin release. Ang 1–7 also evoked vasodilation in isolated perfused mouse hearts involving interaction of Mas with AT1- and AT2-related mechanisms. Together, these data suggest that Ang 1–7 is a vasorelaxant peptide in the coronary bed and that this effect involves coupling to Mas and release of NO and prostaglandins.
Nevertheless, because Neves et al. found that, at high concentrations (>25 nM), Ang 1–7 induces a concentration-dependent decrease in coronary flow in isolated perfused rat hearts, it remains to be demonstrated whether Ang 1–7 directly causes vasodilation in the coronary bed. This effect was not accompanied by consistent changes in contraction force and heart rate. A similar finding was observed in isolated hamster hearts. The other of the most important beneficial effects of Ang 1–7 is its ability to regulate the expression of extracellular matrix (ECM) proteins and cardiac remodeling. Iwata et al. reported that Ang 1–7 binds to isolated adult rat cardiac fibroblasts, which play a critical role in cardiac remodeling. Treatment of these cells with Ang 1–7 inhibited Ang II-induced increases in collagen synthesis [Figure 3]. Importantly, deletion of Mas produced impairment of cardiac function associated with a significant increase in collagen Type I, III and fibronectin content in the heart., On the other hand, Ang 1–7 also attenuated either fetal bovine serum- or endothelin 1-stimulated 3 H-leucine incorporation into isolated neonatal rat cardiac myocytes through a mechanism involving inhibition of serum-stimulated extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activity and activation of Mas. Chronic administration of this peptide significantly attenuated LV hypertrophy and fibrosis in pressure-overloaded rats  and fibrosis in Ang II-infused and deoxycorticosterone acetate-salt rats., In addition, these animals showed a slight, but significant, increase in daily and nocturnal dP/dt, more resistance to isoproterenol-induced cardiac hypertrophy, reduced duration of reperfusion arrhythmias, and improved postischemic function in isolated perfused hearts, further supporting a beneficial role for Ang 1–7 in cardiac function at physiological concentrations. Altogether, these findings indicate that the ACE II/Ang 1–7/Mas axis is a functional cardioprotective arm of the RAS [Figure 4]. The signal transduction pathways following activation of Mas in the heart are not fully characterized but probably involve release of prostacyclin and/or NO release ,, since Ang 1–7 stimulated NO production and activated endothelial NO synthase and Akt in cardiomyocytes. Of note, the antihypertrophic effects of Ang 1–7 on Ang II-treated cardiomyocytes were prevented by the blockade of the NO/cGMP pathway. Moreover, amplification of the actions of BK , and decrease of Ang II levels in the heart , may also be possible mechanisms involved in the beneficial cardiac effects of Ang 1–7.
|Figure 3: Angiotensin II-induced cardiac fibrosis and hypertrophy under pathological conditions. Angiotensin II acts on cell-specific receptors on cardiomyocytes and fibroblasts. Mast cell production of human heart chymase may present an alternative pathway|
Click here to view
|Figure 4: Opposing cardiovascular effects of the two major peptides of the renin–angiotensin system, angiotensin II and angiotensin 1–7. The intersection between these two arms of the system is the angiotensin-converting enzyme II since this enzyme can cleave the vasoconstrictor/proliferative peptide angiotensin II to form the vasodilator/antiproliferative fragment angiotensin 1–7|
Click here to view
| Application of Cardioprotective Effects of Ace Ii|| |
Application of cardioprotective effects of ACE II in animal studies
Several observations and experimental evidence from animal models have suggested a beneficial role of the ACE II-Ang 1–7 axis on cardiovascular function. Elevated ACE II expression appears to occur at the initial stage of several pathologic conditions and declines with disease progression. Loss of ACE II enhances the susceptibility to myocardial dysfunction, while enhancing ACE II action prevents adverse pathological remodeling and slows the progression to HF., Mechanistically, loss of ACE II may also trigger activation of the myocardial NADPH oxidase system, increased production of superoxide, and activation of matrix metalloproteinases (MMPs), leading to further adverse myocardial remodeling and dysfunction. Animal studies have directly demonstrated a potentially critical role of ACE II in counterbalancing the maladaptive pathophysiological effects of Ang II., In the heart, ACE II appears to be the primary pathway for the metabolism of Ang II. At the same time, excess Ang II may promote its increase conversion to Ang 1–7 in the presence of ACE II. Hence, a deficiency of ACE II can lead to increased tissue and circulating levels of Ang II and reduced levels of Ang 1–7 as demonstrated in animal models, which result in early cardiac hypertrophy and fibrosis that is reversible with double knockout (DKO) mice of ACE and ACE II genes or following treatment with ACE inhibitors or angiotensin receptor blockers (ARBs)., Overexpression of ACE II prevents adverse cardiac remodeling, and treatment with Ang 1–7 prevents cardiac fibrosis in animal models. Consistent with a key role of ACE II in post-MI remodeling, overexpression of ACE II ameliorates LV remodeling and dysfunction in a rat model of MI. On the other hand, loss of ACE II worsens the pathological remodeling and results in a rapid progression to reduced systolic function and HF in a pressure-overload mouse model. These observations suggest that ACE II could be an important regulator of LV remodeling.
Application of cardioprotective effects of ACE II in human
Role of ACE II in cardiac remodeling and systolic dysfunction in humans
Cardiac remodeling of the heart plays a key role in the progressive deterioration of cardiac function that leads to human HF. In patients with HF, elevated levels of Ang II, and myocardial ACE, mRNA level activity has been reported. On the other hand, the role of ACE II expression in the development of LV remodeling in human HF remained poorly understood. The first evidence of ACE II-mediated formation of Ang 1–7 in human HF came from ACE II protein and substrate activity analyses of explanted human heart tissues. They found that Ang 1–7-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was NEP-like whereas ACE II appears to favor Ang II. ACE II expression is increased regardless of etiology. Meanwhile, the relationship between the expression of ACE II mRNA and the severity of LV remodeling was investigated in 14 patients with end-stage HF. Interestingly, there was a strong relationship between the amount of ACE II gene expression and the severity of LV remodeling determined by LV dimensions, suggesting that ACE II expression could be activated as an adaptive compensatory mechanism to militate against LV remodeling. However, ACE II expression did not correlate with either LV ejection fraction or plasma brain natriuretic peptide levels, which implies that such compensatory increase in expression of ACE II may be insufficient to counter pathologic processes as disease is progressed. The clinical relevance of ACE II in the setting of systolic dysfunction was further demonstrated by the detection of soluble ACE II (sACE II) activity in patients with systolic HF. Increasing sACE II plasma activity strongly correlated with a clinical diagnosis of HF regardless of etiology and tracked with worsening functional class and higher natriuretic peptide levels, while independent of other disease states and medication use. In a separate cohort of 113 patients with chronic systolic HF with detailed echocardiographic analysis, higher sACE II activity was associated with a lower LV ejection fraction, more right ventricular systolic dysfunction, and larger LV end-diastolic diameter.
Furthermore, sACE II was an independent predictor of adverse clinical events (death, cardiac transplant, and HF hospitalizations), independently of LV ejection fraction and natriuretic peptide levels. These findings have now been substantiated in several independent confirmatory studies., The impact of drug therapy on directly modulating ACE II activity and expression has not been well described. In the setting of acute decompensated HF in patients with advanced HF, circulating sACE II activity was found to increase following intensive medical therapy aiming to optimize hemodynamic derangements and relief congestion. Interestingly, patients who experienced >50% increase in their sACE II activity were associated with better long-term outcomes, further supporting the potential counter-regulatory role of ACE II. Conventional drugs such as ARBs and mineralocorticoid receptor antagonists (MRAs) have been reported to increase ACE II-related beneficial effects, thus providing an additional rationale for their use in the setting of HF. From this perspective, ARBs would appear to have an advantage since they tend to increase Ang II levels, an effect that along with its promotion of ACE II activity would raise the levels of the protective peptide Ang 1–7. However, superiority of the ARBs over ACE inhibitors in either MI survivors or HF patients has yet to be demonstrated in large clinical trials, suggesting that the perceived incremental benefit may not be as clinically relevant. Meanwhile, MRA decreased ACE and increased ACE II. Each and both are capable of reducing Ang II level. Studies demonstrating incremental benefit of MRAs in patients with systolic HF have supported its broad adoption, yet to our knowledge, no studies on long-term effects of MRA on ACE II or Ang 1–7 metabolism and effects in humans have been conducted.
Role of ACE II in diastolic dysfunction and hypertension
Epidemiological studies have consistently demonstrated that HF with preserved ejection fraction (HFpEF) accounts for over 30% of all HF, particularly in elderly patients. The development of myocardial fibrosis and pathological hypertrophy has been the central hypothesis that contributes to the development of diastolic dysfunction and HFpEF due to increased myocardial stiffness. Indeed, elevated sACE II levels have been observed in patients with HFpEF as well. As previously discussed, ACE II negatively regulates the pathophysiological effects of a pressor and suppressor dose of Ang II on myocardial structure and function.
ACE II is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction. With the paucity of effective drug therapies, strategies to enhance ACE II effects in patients with HFpEF are promising although studies showing reversal and recovery of myocardial stiffness after its development are lacking. Several studies have demonstrated the modulatory effect of ACE II on blood pressure. ACE II is present in vascular endothelial walls and plays a major role in producing Ang 1–7. Based onin vitro biochemical data andin vivo findings, a reduction in ACE II levels could lead to elevated Ang II levels, thus promoting increased blood pressure., Overexpression of ACE II in the vasculature reduces blood pressure and improves endothelial function in hypertensive rats. Moreover, interventions to augment the expression or activity of ACE II have been shown to significantly reduce blood pressure levels. However, data associated with ACE II polymorphism to hypertension are controversial, with some studies conceding a possible association with LV mass, septal wall thickness, and hypertrophy, while others refute that association.,, Meanwhile, the vasodilatory effects of Ang 1–7 are attributed to stimulating the production of NO, prostaglandins, and endothelium-derived relaxation factors. In humans, Ang 1–7 elicited a direct vasodilation in the forearm circulation of both normotensive and hypertensive patients. Interestingly, Ang 1–7 levels are elevated with treatment of ACE inhibitors and ARB, which might suggest the contribution of this peptide in their antihypertensive effects. Localized ACE II/Ang 1–7 axis in the brain may also modulate centrally mediated hypertension.
ACE II as a potential therapy for heart failure
The negative regulatory role of ACE II in RAS has made it an important therapeutic target in the control of cardiovascular diseases (CVDs). Oudit et al. reported the loss of ACE II in Ace II −/y mutant mice lead to an age-dependent and progressive decline in cardiac function associated with ventricular dilation at 6 and 12 months of age. These results collectively demonstrated that loss of ACE II enhances the susceptibility to HF by Ang II-mediated injury through AT1R and PI3Kγ. A similar result was recognized with the mice lacking ACE II (Ace II −/y mice) that exhibited reduced cardiac contractility and developed cardiac hypertrophy and dilatation in response to transverse aortic constriction.
Localization of ACE II in the heart and significant activation of cardiac ACE II after MI suggest the importance of ACE II in cardiac function, and that ACE II may combat the adverse effects of a locally activated cardiac RAS. Thus, the question is whether ACE II deficiency compromises the cardiac response to MI. To clarify this, ACE II-KO (Ace II −/y) mice and wild-type littermates (ACE II +/y) were used and were subjected to either left anterior descending coronary artery ligation or sham surgery. The results demonstrated that loss of ACE II is associated with increased mortality and infarct expansion with adverse ventricular remodeling and were associated with greater oxidative stress, MMP activation, and inflammation. Collectively, these results support the hypothesis that enhancing ACE II activity would serve to minimize adverse post-MI ventricular remodeling. This is in agreement with the study by Der Sarkissian et al., who showed that cardiac overexpression of ACE II exerts a protective influence on the heart during MI by preserving cardiac functions, LV wall motion, and contractility and by attenuating LV wall thinning. Also, in order to understand mechanism of the adverse remodeling and increased propensity to develop HF, study by Parajuli et al has examined the role of p47phox subunit in the exaggerated oxidative stress response in pressure overloaded male ACE II-KO mice. The double-mutant mice (DKO) lacking ACE II and p47phox genes (ACE II 2/y/p47phox 2/2) were subjected to aortic constriction. The reversal of pathological hypertrophy and systolic dysfunction in the DKO mice indicated that the adverse remodeling of the myocardial ECM was minimized. These results showed that the adverse myocardial remodeling in ACE II-KO mice in response to biomechanical stress was clearly NADPH oxidase-dependent, with a dominant role being played by the p47 phox subunit. ACE II also plays a pivotal role in the suppression of diabetes-associated cardiac complications. Cardiac and vascular structure and function, Ang II metabolism, signaling, and tissue-reactive oxygen species generation were investigated in insulin-deficient diabetic Akita mice in response to genetic ablation of ACE II. In this report, loss of ACE II-mediated disruption of the balance of the RAS in a diabetic state was observed. Further, it led to Ang II–AT1R axis-dependent systolic dysfunction and impaired vascular function in ACE II-disrupted mice, which demonstrated the protective mechanism elicited by ACE II against diabetes-induced cardiovascular complications. The knowledge concerning ACE II, gained over a decade, emphasizes how it can be used for translational purposes.
The molecular and biological mechanisms mediated by ACE II can operate simultaneously within the context of any specific organ or cell. Importantly, the effects mediated by ACE II can be attributed to suppressed activation of the Ang II–AT1R axis and (or) stimulation of the Ang 1–7 Mas receptor (MasR) axis. To understand the relative importance of both the axes, another study on pressure and volume overload model in ACE II null (Ace II-KO) mice and treated them with irbesartan or Ang 1–7 shows that there is functional redundancy in the cardioprotective effects of irbesartan as well as Ang 1–7, as shown by the suppression of NADPH oxidase activity, activation of MMP2 and MMP9, and pathological signaling, suggesting the equal importance of both the axes. These data and other studies focusing on the Ang 1–7 MasR axis in cardiac diseases support the importance of activation of the Ang 1–7 MasR axis.,,, This could be achieved by Ang 1–7 supplementation and genetic delivery of MasR agonism using AVE 0991.,, However, the comparative therapeutic benefits of ACE II treatment compared with activating the Ang 1–7 MasR axis need to be studied. The development of CVD is known to be gender specific as men are more likely to have a coronary event than women. The location of the ACE II gene on the X chromosome encompasses an area where genes are known to escape from X-chromosome inactivation and that could make the women less prone to coronary events. Thus, when considering ACE II therapy for CVD, the gender of an individual should be considered. This is probably due to sex differences in the posttranscriptional and posttranslational mechanisms of gene regulation. Considering formulations, the clinical use of ACE II is limited as it is a peptide that undergoes rapid proteolytic degradation in the circulation. Pharmacological and cell-based strategies aimed at increasing vascular ACE II bioavailability may represent a new therapeutic avenue in the treatment of CVD. ACE II activators, for example, resorcinolnaphthalein or 1-([2-dimethylamino] ethylamino)-4-[hydroxymethyl]-7-([4-methylphenyl] sulfonyl oxy)-9H-xanthene-9-one, have shown promising results in animal models of diabetic cardiovascular complications., In contrast, recombinant human ACE II (rhACE II) has also shown cardioprotective effects on different preclinical models of systolic as well as diastolic HF. However, chronic administration of recombinant proteins has its own complications, and that needs to be tested for rhACE II.
The adenoviral delivery of ACE II seems to be the most interesting approach for ACE II therapy as adenovirus-mediated Ace II gene delivery offers local ACE II delivery that is hypothesized to provide greater therapeutic benefits compared with systemic ACE II delivery. Thus, increased knowledge of the local and systemic RAS warrants comparison among the different modes of ACE II activation, particularly systemic administration, for example, rhACE II, ACE II activator, and local ACE II delivery, for example, adenoviral ACE II delivery.
| Conclusion|| |
ACE II is a new component of the RAS. This transmembrane protease has emerged as a negative regulator of the RAS that counterbalances the multiple functions of ACE. Because ACE II efficiently hydrolyzes the potent vasoconstrictor Ang II to Ang 1–7, this has changed overall perspective about the classical view of the RAS because it represents the first example of a feed-forward mechanism directed toward mitigation of the actions of Ang II. Ang 1–7 appears to play a central role in the RAS because it exerts a vast array of actions; many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. It is now generally accepted that the RAS is dual and that, besides the well-known mainly deleterious arm if stimulated excessively (ACE/Ang II/AT1), there is a second beneficial axis consisting of ACE II, Ang 1–7, and Mas to recorrect the deleterious arm. A summary of the evidence from both experimental and clinical studies shows that the overall biological role of ACE II/Ang 1–7/Mas axis has a protective role within normal function of heart [Figure 5]. Therefore, the development of drugs that could activate ACE II function would allow extending treatment options in hypertension, HF, and other CVDs.
|Figure 5: Potential protective effects of angiotensin-converting enzyme II and angiotensin 1–7 on pathological cardiac remodeling and heart failure. ACE II: Angiotensin-converting enzyme II, Ang: Angiotensin|
Click here to view
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Piepho RW, Beal J. An overview of antihypertensive therapy in the 20th
century. J Clin Pharmacol 2000;40:967-77.
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000;275:33238-43.
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al.
Anovel angiotensin-converting enzyme-related carboxypeptidase (ACE II) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87:E1-9.
Guang C, Phillips RD, Jiang B, Milani F. Three key proteases – Angiotensin-I-converting enzyme (ACE), ACE II and renin – Within and beyond the renin-angiotensin system. Arch Cardiovasc Dis 2012;105:373-85.
Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J 2013;77:301-8.
Clarke NE, Turner AJ. Angiotensin-converting enzyme 2: The first decade. Int J Hypertens 2012;2012:307315.
Guy JL, Jackson RM, Jensen HA, Hooper NM, Turner AJ. Identification of critical active-site residues in angiotensin-converting enzyme-2 (ACE II) by site-directed mutagenesis. FEBS J 2005;272:3512-20.
Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, et al.
Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE II and is developmentally regulated in embryonic kidneys. J Biol Chem 2001;276:17132-9.
Guy JL, Jackson RM, Acharya KR, Sturrock ED, Hooper NM, Turner AJ. Angiotensin-converting enzyme-2 (ACE II): Comparative modeling of the active site, specificity requirements, and chloride dependence. Biochemistry 2003;42:13185-92.
Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al.
Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002;277:14838-43.
Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family: Genomics and pharmacology. Trends Pharmacol Sci 2002;23:177-83.
Yagil Y, Yagil C. Hypothesis: ACE II modulates blood pressure in the mammalian organism. Hypertension 2003;41:871-3.
Ocaranza MP, Godoy I, Jalil JE, Varas M, Collantes P, Pinto M, et al.
Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006;48:572-8.
Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 2005;289:H2281-90.
Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: New players of the renin-angiotensin system. J Endocrinol 2013;216:R1-17.
Campbell DJ, Zeitz CJ, Esler MD, Horowitz JD. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE II) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens 2004;22:1971-6.
Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM. Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone. Clin Cancer Res 2009;15:7398-404.
Yamada K, Iyer SN, Chappell MC, Ganten D, Ferrario CM. Converting enzyme determines plasma clearance of angiotensin-(1-7). Hypertension 1998;32:496-502.
Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al.
Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A 2003;100:8258-63.
Iusuf D, Henning RH, van Gilst WH, Roks AJ. Angiotensin-(1-7): Pharmacological properties and pharmacotherapeutic perspectives. Eur J Pharmacol 2008;585:303-12.
Zimmerman D, Burns KD. Angiotensin-(1-7) in kidney disease: A review of the controversies. Clin Sci (Lond) 2012;123:333-46.
Giani JF, Mayer MA, Muñoz MC, Silberman EA, Höcht C, Taira CA, et al.
Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats. Am J Physiol Endocrinol Metab 2009;296:E262-71.
Echeverría-Rodríguez O, Del Valle-Mondragón L, Hong E. Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo
. Peptides 2014;51:26-30.
Santos SH, Braga JF, Mario EG, Pôrto LC, Rodrigues-Machado Mda G, Murari A, et al.
Improved lipid and glucose metabolism in transgenic rats with increased circulating angiotensin-(1-7). Arterioscler Thromb Vasc Biol 2010;30:953-61.
Hoogwerf BJ. Renin-angiotensin system blockade and cardiovascular and renal protection. Am J Cardiol 2010;105 1 Suppl: 30A-5A.
Herichova I, Szantoova K. Renin-angiotensin system: Upgrade of recent knowledge and perspectives. Endocr Regul 2013;47:39-52.
Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin system: A target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol 2012;302:H1219-30.
Nguyen Dinh Cat A, Touyz RM. A new look at the renin-angiotensin system – Focusing on the vascular system. Peptides 2011;32:2141-50.
Xia H, Lazartigues E. Angiotensin-converting enzyme 2 in the brain: Properties and future directions. J Neurochem 2008;107:1482-94.
Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, et al.
Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 2010;106:373-82.
Xia H, Feng Y, Obr TD, Hickman PJ, Lazartigues E. Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice. Hypertension 2009;53:210-6.
Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, et al.
The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2010;182:1065-72.
Raizada MK, Ferreira AJ. ACE II: A new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol 2007;50:112-9.
Komatsu T, Suzuki Y, Imai J, Sugano S, Hida M, Tanigami A, et al
. Molecular cloning, mRNA expression and chromosomal localization of mouse angiotensin-converting enzyme-related carboxypeptidase (mACE II). DNA Seq 2002;13:217-20.
Harmer D, Gilbert M, Borman R, Clark KL. Quantitative mRNA expression profiling of ACE II, a novel homologue of angiotensin converting enzyme. FEBS Lett 2002;532:107-10.
Gembardt F, Sterner-Kock A, Imboden H, Spalteholz M, Reibitz F, Schultheiss HP, et al.
Organ-specific distribution of ACE II mRNA and correlating peptidase activity in rodents. Peptides 2005;26:1270-7.
Oudit GY, Crackower MA, Backx PH, Penninger JM. The role of ACE II in cardiovascular physiology. Trends Cardiovasc Med 2003;13:93-101.
Tikellis C, Wookey P, Candido R, Andrikopoulos S, Thomas M. Improved islet morphology after blockade of the reninangiotensin system in the ZDF rat. Diabetes 2004;53:989-97.
Bindom SM, Hans CP, Xia H, Boulares AH, Lazartigues E. Angiotensin I-converting enzyme type 2 (ACE II) gene therapy improves glycemic control in diabetic mice. Diabetes 2010;59:2540-8.
Fang HJ, Yang JK. Tissue-specific pattern of angiotensin-converting enzyme 2 expression in rat pancreas. J Int Med Res 2010;38:558-69.
Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, et al.
Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005;54:1790-6.
Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T, et al.
ACE II X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem 2004;279:17996-8007.
Grinstead WC, Young JB. The myocardial renin-angiotensin system: Existence, importance, and clinical implications. Am Heart J 1992;123(4 Pt 1):1039-45.
Dostal DE, Baker KM. The cardiac renin-angiotensin system: Conceptual, or a regulator of cardiac function? Circ Res 1999;85:643-50.
Sawa H, Tokuchi F, Mochizuki N, Endo Y, Furuta Y, Shinohara T, et al.
Expression of the angiotensinogen gene and localization of its protein in the human heart. Circulation 1992;86:138-46.
Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: Potential roles in cardiovascular and renal regulation. Endocr Rev 2003;24:261-71.
Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI, Mendelsohn AO. Localization of angiotensin converting enzyme in rat heart. Circ Res 1991;68:141-9.
Pagliaro P, Penna C. Rethinking the renin-angiotensin system and its role in cardiovascular regulation. Cardiovasc Drugs Ther 2005;19:77-87.
Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, et al.
Myocardial infarction increases ACE II expression in rat and humans. Eur Heart J 2005;26:369-75.
Neves LA, Almeida AP, Khosla MC, Santos RA. Metabolism of angiotensin I in isolated rat hearts. Effect of angiotensin converting enzyme inhibitors. Biochem Pharmacol 1995;50:1451-9.
Mahmood A, Jackman HL, Teplitz L, Igic R. Metabolism of angiotensin I in the coronary circulation of normal and diabetic rats. Peptides 2002;23:1171-5.
Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al.
Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002;417:822-8.
Yamamoto K, Ohishi M, Katsuya T, Ito N, Ikushima M, Kaibe M, et al.
Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 2006;47:718-26.
Gurley S, Allred A, Le T, Griffiths R, Mao L, Philip N, et al
. Altered blood pressure responses and normal cardiac phenotype in ACE II-null mice. J Clin Invest 2006;116:2218-25.
Zisman LS, Meixell GE, Bristow MR, Canver CC. Angiotensin-(1-7) formation in the intact human heart:In vivo
dependence on angiotensin II as substrate. Circulation 2003;108:1679-81.
Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE II gene expression is up-regulated in the human failing heart. BMC Med 2004;2:19.
Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004;43:970-6.
Diez-Freire C, Vazquez J, Correa de Adjounian M, Ferrari M, Yuan L, Silver X, et al
. ACE II gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics 2006;27:12-9.
Huentelman MJ, Grobe JL, Vazquez J, Stewart JM, Mecca AP, Katovich MJ, et al.
Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE II in rats. Exp Physiol 2005;90:783-90.
Dias-Peixoto MF, Santos RA, Gomes ER, Alves MN, Almeida PW, Greco L, et al.
Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes. Hypertension 2008;52:542-8.
Santos RA, Brum JM, Brosnihan KB, Ferrario CM. The renin-angiotensin system during acute myocardial ischemia in dogs. Hypertension 1990;15 2 Suppl:I121-7.
Averill DB, Ishiyama Y, Chappell MC, Ferrario CM. Cardiac angiotensin-(1-7) in ischemic cardiomyopathy. Circulation 2003;108:2141-6.
Ferreira AJ, Bader M, Santos RA. Therapeutic targeting of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas cascade in the renin-angiotensin system: A patent review. Expert Opin Ther Pat 2012;22:567-74.
Garabelli PJ, Modrall JG, Penninger JM, Ferrario CM, Chappell MC. Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart. Exp Physiol 2008;93:613-21.
Danser AH, Saris JJ, Schuijt MP, van Kats JP. Is there a local renin-angiotensin system in the heart? Cardiovasc Res 1999;44:252-65.
De Mello WC, Cherry RC, Manivannan S. Electrophysiologic and morphologic abnormalities in the failing heart: Effect of enalapril on the electrical properties. J Card Fail 1997;3:53-61.
De Mello WC. Cell coupling and impulse propagation in the failing heart. J Cardiovasc Electrophysiol 1999;10:1409-20.
De Mello WC, Crespo MJ. Correlation between changes in morphology, electrical properties, and angiotensin-converting enzyme activity in the failing heart. Eur J Pharmacol 1999;378:187-94.
Hein L, Stevens ME, Barsh GS, Pratt RE, Kobilka BK, Dzau VJ. Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc Natl Acad Sci U S A 1997;94:6391-6.
Dodge SM, Beardslee MA, Darrow BJ, Green KG, Beyer EC, Saffitz JE. Effects of angiotensin II on expression of the gap junction channel protein connexin43 in neonatal rat ventricular myocytes. J Am Coll Cardiol 1998;32:800-7.
Donoghue M, Wakimoto H, Maguire CT, Acton S, Hales P, Stagliano N, et al.
Heart block, ventricular tachycardia, and sudden death in ACE II transgenic mice with downregulated connexins. J Mol Cell Cardiol 2003;35:1043-53.
De Mello WC. Angiotensin (1-7) re-establishes impulse conduction in cardiac muscle during ischaemia-reperfusion. The role of the sodium pump. J Renin Angiotensin Aldosterone Syst 2004;5:203-8.
López Ordieres MG, Gironacci M, Rodríguez de Lores Arnaiz G, Peña C. Effect of angiotensin-(1-7) on ATPase activities in several tissues. Regul Pept 1998;77:135-9.
Ferreira AJ, Santos RA, Almeida AP. Angiotensin-(1-7): Cardioprotective effect in myocardial ischemia/reperfusion. Hypertension 2001;38(3 Pt 2):665-8.
Ferreira AJ, Santos RA, Almeida AP. Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts. Braz J Med Biol Res 2002;35:1083-90.
Neves LA, Almeida AP, Khosla MC, Campagnole-Santos MJ, Santos RA. Effect of angiotensin-(1-7) on reperfusion arrhythmias in isolated rat hearts. Braz J Med Biol Res 1997;30:801-9.
Oudot A, Vergely C, Ecarnot-Laubriet A, Rochette L. Pharmacological concentration of angiotensin-(1-7) activates NADPH oxidase after ischemia-reperfusion in rat heart through AT1 receptor stimulation. Regul Pept 2005;127:101-10.
Gironacci MM, Adler-Graschinsky E, Peña C, Enero MA. Effects of angiotensin II and angiotensin-(1-7) on the release of [3H] norepinephrine from rat atria. Hypertension 1994;24:457-60.
Ferreira AJ, Castro CH, Guatimosim S, Almeida PW, Gomes ER, Dias-Peixoto MF, et al.
Attenuation of isoproterenol-induced cardiac fibrosis in transgenic rats harboring an angiotensin-(1-7)-producing fusion protein in the heart. Ther Adv Cardiovasc Dis 2010;4:83-96.
Eriksson U, Danilczyk U, Penninger JM. Just the beginning: Novel functions for angiotensin-converting enzymes. Curr Biol 2002;12:R745-52.
Heusch G. Hibernating myocardium. Physiol Rev 1998;78:1055-85.
Murphy AM, Kögler H, Georgakopoulos D, McDonough JL, Kass DA, Van Eyk JE, et al.
Transgenic mouse model of stunned myocardium. Science 2000;287:488-91.
Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 2001;61:6669-73.
Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 1999;94:4177-85.
Giordano FJ, Gerber HP, Williams SP, VanBruggen N, Bunting S, Ruiz-Lozano P, et al.
Acardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci U S A 2001;98:5780-5.
van Kats JP, Methot D, Paradis P, Silversides DW, Reudelhuber TL. Use of a biological peptide pump to study chronic peptide hormone action in transgenic mice. Direct and indirect effects of angiotensin II on the heart. J Biol Chem 2001;276:44012-7.
Loot AE, Roks AJ, Henning RH, Tio RA, Suurmeijer AJ, Boomsma F, et al.
Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 2002;105:1548-50.
Wiemer G, Dobrucki LW, Louka FR, Malinski T, Heitsch H. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension 2002;40:847-52.
Pinheiro SV, Simões e Silva AC, Sampaio WO, de Paula RD, Mendes EP, Bontempo ED, et al.
Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension 2004;44:490-6.
Lemos VS, Silva DM, Walther T, Alenina N, Bader M, Santos RA. The endothelium-dependent vasodilator effect of the nonpeptide Ang (1-7) mimic AVE 0991 is abolished in the aorta of Mas-knockout mice. J Cardiovasc Pharmacol 2005;46:274-9.
Ferreira AJ, Oliveira TL, Castro MC, Almeida AP, Castro CH, Caliari MV, et al.
Isoproterenol-induced impairment of heart function and remodeling are attenuated by the nonpeptide angiotensin-(1-7) analogue AVE 0991. Life Sci 2007;81:916-23.
Ferreira AJ, Jacoby BA, Araújo CA, Macedo FA, Silva GA, Almeida AP, et al.
The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE-0991 attenuates heart failure induced by myocardial infarction. Am J Physiol Heart Circ Physiol 2007;292:H1113-9.
Benter IF, Yousif MH, Anim JT, Cojocel C, Diz DI. Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol 2006;290:H684-91.
Marques FD, Ferreira AJ, Sinisterra RD, Jacoby BA, Sousa FB, Caliari MV, et al.
An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension 2011;57:477-83.
Marques FD, Melo MB, Souza LE, Irigoyen MC, Sinisterra RD, de Sousa FB, et al.
Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats. Int J Hypertens 2012;2012:795452.
Santos RA, Campagnole-Santos MJ, Andrade SP. Angiotensin-(1-7): An update. Regul Pept 2000;91:45-62.
Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 1996;27(3 Pt 2):523-8.
Pörsti I, Bara AT, Busse R, Hecker M. Release of nitric oxide by angiotensin-(1-7) from porcine coronary endothelium: Implications for a novel angiotensin receptor. Br J Pharmacol 1994;111:652-4.
Gorelik G, Carbini LA, Scicli AG. Angiotensin 1-7 induces bradykinin-mediated relaxation in porcine coronary artery. J Pharmacol Exp Ther 1998;286:403-10.
Almeida AP, Frábregas BC, Madureira MM, Santos RJ, Campagnole-Santos MJ, Santos RA. Angiotensin-(1-7) potentiates the coronary vasodilatatory effect of bradykinin in the isolated rat heart. Braz J Med Biol Res 2000;33:709-13.
Castro CH, Santos RA, Ferreira AJ, Bader M, Alenina N, Almeida AP. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension 2005;46:937-42.
Kumagai H, Khosla M, Ferrario C, Fouad-Tarazi FM. Biological activity of angiotensin-(1-7) heptapeptide in the hamster heart. Hypertension 1990;15 2 Suppl:I29-33.
Iwata M, Cowling RT, Gurantz D, Moore C, Zhang S, Yuan JX, et al.
Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol 2005;289:H2356-63.
Santos RA, Castro CH, Gava E, Pinheiro SV, Almeida AP, Paula RD, et al.
Impairment ofin vitro
heart function in angiotensin-(1-7) receptor MAS knockout mice. Hypertension 2006;47:996-1002.
Gava E, de Castro CH, Ferreira AJ, Colleta H, Melo MB, Alenina N, et al.
Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart. Regul Pept 2012;175:30-42.
Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the Mas receptor. Am J Physiol Heart Circ Physiol 2005;289:H1560-6.
Wang LJ, He JG, Ma H, Cai YM, Liao XX, Zeng WT, et al.
Chronic administration of angiotensin-(1-7) attenuates pressure-overload left ventricular hypertrophy and fibrosis in rats. Di Yi Jun Yi Da Xue Xue Bao 2005;25:481-7.
Grobe JL, Mecca AP, Mao H, Katovich MJ. Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension. Am J Physiol Heart Circ Physiol 2006;290:H2417-23.
Grobe JL, Mecca AP, Lingis M, Shenoy V, Bolton TA, Machado JM, et al.
Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7). Am J Physiol Heart Circ Physiol 2007;292:H736-42.
Santos RA, Ferreira AJ, Nadu AP, Braga AN, de Almeida AP, Campagnole-Santos MJ, et al.
Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats. Physiol Genomics 2004;17:292-9.
Gomes ER, Lara AA, Almeida PW, Guimarães D, Resende RR, Campagnole-Santos MJ, et al.
Angiotensin-(1-7) prevents cardiomyocyte pathological remodeling through a nitric oxide/guanosine 3',5'-cyclic monophosphate-dependent pathway. Hypertension 2010;55:153-60.
Mendes AC, Ferreira AJ, Pinheiro SV, Santos RA. Chronic infusion of angiotensin-(1-7) reduces heart angiotensin II levels in rats. Regul Pept 2005;125:29-34.
Nadu AP, Ferreira AJ, Reudelhuber TL, Bader M, Santos RA. Reduced isoproterenol-induced renin-angiotensin changes and extracellular matrix deposition in hearts of TGR (A1-7) 3292 rats. J Am Soc Hypertens 2008;2:341-8.
Chamsi-Pasha MA, Shao Z, Tang WH. Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep 2014;11:58-63.
Tikellis C, Bernardi S, Burns WC. Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease. Curr Opin Nephrol Hypertens 2011;20:62-8.
Oudit GY, Kassiri Z, Patel MP, Chappell M, Butany J, Backx PH, et al.
Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE II null mice. Cardiovasc Res 2007;75:29-39.
Bodiga S, Zhong J, Wang W. Enhanced susceptibility to biomechanical stress in ACE II null mice is prevented by loss of the p47(phox) NADPH oxidase subunit. Cardiovasc Res 2011;91:151-61.
Santos RA, Ferreira AJ, Simões e Silva AC. Recent advances in the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis. Exp Physiol 2008;93:519-27.
Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE II of the heart: From angiotensin I to angiotensin (1-7). Cardiovasc Res 2007;73:463-9.
Grobe JL, Der Sarkissian S, Stewart JM, Meszaros JG, Raizada MK, Katovich MJ. ACE II overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci (Lond) 2007;113:357-64.
Zhao YX, Yin HQ, Yu QT, Qiao Y, Dai HY, Zhang MX, et al.
ACE II overexpression ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction. Hum Gene Ther 2010;21:1545-54.
Lazartigues E, Feng Y, Lavoie JL. The two fACEs of the tissue renin-angiotensin systems: Implication in cardiovascular diseases. Curr Pharm Des 2007;13:1231-45.
Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM. Angiotensin-converting enzyme 2 (ACE II) in disease pathogenesis. Circ J 2010;74:405-10.
Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, et al.
Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: Evidence for upregulation of the angiotensin-converting enzyme Homologue ACE II. Circulation 2003;108:1707-12.
Ohtsuki M, Morimoto S, Izawa H, Ismail TF, Ishibashi-Ueda H, Kato Y, et al.
Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure. Int J Cardiol 2010;145:333-4.
Epelman S, Tang WH, Chen SY, Van Lente F, Francis GS, Sen S. Detection of soluble angiotensin-converting enzyme 2 in heart failure: Insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol 2008;52:750-4.
Epelman S, Shrestha K, Troughton RW, Francis GS, Sen S, Klein AL, et al.
Soluble angiotensin-converting enzyme 2 in human heart failure: Relation with myocardial function and clinical outcomes. J Card Fail 2009;15:565-71.
Wang Y, Moreira Mda C, Heringer-Walther S, Ebermann L, Schultheiss HP, Wessel N, et al.
Plasma ACE II activity is an independent prognostic marker in Chagas' disease and equally potent as BNP. J Card Fail 2010;16:157-63.
Shao Z, Shrestha K, Borowski AG, Kennedy DJ, Epelman S, Thomas JD, et al.
Increasing serum soluble angiotensin-converting enzyme 2 activity after intensive medical therapy is associated with better prognosis in acute decompensated heart failure. J Card Fail 2013;19:605-10.
Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, et al.
Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res 2005;97:946-53.
Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, et al.
Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 2010;122:717-28.
Wang W, Bodiga S, Das SK, Lo J, Patel V, Oudit GY. Role of ACE II in diastolic and systolic heart failure. Heart Fail Rev 2012;17:683-91.
Wysocki J, Ye M, Rodriguez E, González-Pacheco FR, Barrios C, Evora K, et al.
Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: Prevention of angiotensin II-dependent hypertension. Hypertension 2010;55:90-8.
Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE II in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 2008;295:H2373-9.
Lu N, Yang Y, Wang Y, Liu Y, Fu G, Chen D, et al.
ACE II gene polymorphism and essential hypertension: An updated meta-analysis involving 11,051 subjects. Mol Biol Rep 2012;39:6581-9.
Vangjeli C, Dicker P, Tregouet DA, Shields DC, Evans A, Stanton AV; MORGAM project. A polymorphism in ACE II is associated with a lower risk for fatal cardiovascular events in females: The MORGAM project. J Renin Angiotensin Aldosterone Syst 2011;12:504-9.
Zhou JB, Yang JK. Meta-analysis of association of ACE II G8790A polymorphism with Chinese Han essential hypertension. J Renin Angiotensin Aldosterone Syst 2009;10:31-4.
Fraga-Silva RA, Costa-Fraga FP, Murça TM, Moraes PL, Martins Lima A, Lautner RQ, et al.
Angiotensin-converting enzyme 2 activation improves endothelial function. Hypertension 2013;61:1233-8.
Der Sarkissian S, Huentelman MJ, Stewart J, Katovich MJ, Raizada MK. ACE II: A novel therapeutic target for cardiovascular diseases. Prog Biophys Mol Biol 2006;91:163-98.
Parajuli N, Ramprasath T, Patel VB, Wang W, Putko B, Mori J, et al.
Targeting angiotensin-converting enzyme 2 as a new therapeutic target for cardiovascular diseases. Can J Physiol Pharmacol 2014;92:558-65.
Burrell LM, Burchill L, Dean RG, Griggs K, Patel SK, Velkoska E. Chronic kidney disease: Cardiac and renal angiotensin-converting enzyme (ACE) II expression in rats after subtotal nephrectomy and the effect of ACE inhibition. Exp Physiol 2012;97:477-85.
Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, et al.
SARS-coronavirus modulation of myocardial ACE II expression and inflammation in patients with SARS. Eur J Clin Invest 2009;39:618-25.
Der Sarkissian S, Grobe JL, Yuan L, Narielwala DR, Walter GA, Katovich MJ, et al.
Cardiac overexpression of angiotensin converting enzyme II protects the heart from ischemia-induced pathophysiology. Hypertension 2008;51:712-8.
Patel VB, Bodiga S, Fan D, Das SK, Wang Z, Wang W, et al.
Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme II-null mice. Hypertension 2012;59:1195-203.
Benter IF, Yousif MH, Cojocel C, Al-Maghrebi M, Diz DI. Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 2007;292:H666-72.
Ebermann L, Spillmann F, Sidiropoulos M, Escher F, Heringer-Walther S, Schultheiss HP, et al.
The angiotensin-(1-7) receptor agonist AVE0991 is cardioprotective in diabetic rats. Eur J Pharmacol 2008;590:276-80.
Qi Y, Shenoy V, Wong F, Li H, Afzal A, Mocco J, et al.
Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology. Exp Physiol 2011;96:863-74.
Flores-Muñoz M, Godinho BM, Almalik A, Nicklin SA. Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the Mas or angiotensin type 2 receptor. PLoS One 2012;7:e45564.
Burrell LM, Harrap SB, Velkoska E, Patel SK. The ACE II gene: Its potential as a functional candidate for cardiovascular disease. Clin Sci (Lond) 2013;124:65-76.
Liu J, Ji H, Zheng W, Wu X, Zhu J, Arnold A, et al
. Sex differences in renal angiotensin converting enzyme 2 (ACE II) activity are 17beta-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ 2010;1:6.
Murça TM, Almeida TC, Raizada MK, Ferreira AJ. Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp Physiol 2012;97:699-709.
Li G, Liu Y, Zhu Y, Liu A, Xu Y, Li X, et al.
ACE II activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats. Lung 2013;191:327-36.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]