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Novel Actions of ACE2

Disclosure: The author is a recipient of grants from the NHLBI of the NIH and has had past unrestricted grant support from Daiichi Sankyo Co., Novartis, Inc., and Merck, Co. He is also a consultant and member of the speaker's bureau of Merck, Co., Novartis, Inc., Sanofi-Aventis, Daiichi Sankyo, Forest Lab., and Astra Zeneca.
Pub Date: Thursday, October 25, 2007
Author: Carlos M. Ferrario, MD

Article Text

Since Tigerstedt and Bergmann first described renin, many advances have occurred regarding the contributions of the renin-angiotensin system (RAS) to the regulation of cardiovascular function and the pathogenesis of cardiovascular disease. Indeed, the effective treatment of hypertension and heart failure arrived almost 100 years after renin's discovery first with the introduction of clinical angiotensin-converting enzyme (ACE) inhibitors in 1981, later with the advent of angiotensin receptor blockers in 1995, and most recently with the development of aliskiren, the first U.S. Food and Drug Administration approved renin inhibitor, in 2007. Throughout this time, interest in the role of angiotensin II (Ang II) as a hormone-inducing pathogen waxed and waned, with many notable scientists and clinicians dismissing its role in cardiovascular medicine. Today, the role of the RAS is firmly established, although debate still exists as to whether all of the important regulatory functions of Ang II can best explain its contribution to the etiopathogenesis of cardiovascular disease.

The discovery by our group that another peptide of the RAS cascade could act as an endogenous inhibitor of Ang II in 1988 was met with much skepticism and has tested the resilience of investigators exploring the functions of angiotensin-(1-7) [Ang-(1-7)]. A search for human homologues of ACE led to the identification of ACE2 from the 5' sequencing of a human heart failure ventricle cDNA library.[1] Two years later, another paper published in the Canadian Journal of Physiology and Pharmacology reported that, unlike somatic ACE, the translated protein contains an N-terminal signal sequence, a single catalytic domain with zinc-binding motif (HEMGH), a transmembrane region, and a small C-terminal cytosolic domain.[2] This study showed that ACE2 is a mono-carboxypeptidase cleaving a single amino acid from Ang I, Ang II, and other peptide substrates. The observation that, in contrast with ACE, ACE2 does not hydrolyze bradykinin and is not inhibited by ACE inhibitors stimulated additional interest in exploring the potential functions of this enzyme in the production of angiotensin peptides and the control of arterial pressure. The same year (2002), a critical step in the further understanding of its role in cardiovascular function was achieved by our demonstration that ACE2 maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension and that, in three salt-sensitive hypertensive rat strains, ACE2 messenger RNA and protein expression are markedly reduced.[3] Improved knowledge regarding the roles of ACE2 in cardiovascular function will markedly affect our understanding of the interplay between the RAS and cardiovascular pathology. The emerging interest in this question is illustrated by the fact that, as of October 2007, a PubMed search for ACE2 retrieves 158 publications (93 of them original articles) by 647 authors in the last 9 years. Given the brevity of this Editorial, it is a daunting task to give proper credit to all. Hence, I summarize here, in somewhat broad terms, the main aspects of research in this field.

ACE2 Enzymatic Characteristics

The human ACE2 gene, consisting of 18 exons, encodes an 805-amino-acid single polypeptide containing an extracellular catalytic domain with two hydrophobic regions a putative 18-amino-acid signal sequence at the N-terminus and a 22-amino-acid membrane anchor near the C-terminus. The extracellular domain contains a central zinc binding motif (HEXXH) with seven potential N-linked glycosylation sites. ACE2 migrates as a polypeptide of Mr 120 000, which is reduced to 85 000 by deglycosylation. ACE2 shares approximately 42% sequence homology and 61% similarity with the N-terminal catalytic domain of ACE.[4,5] Although initial studies implicated ACE2 as acting on Ang I to form Ang-(1-9), Rice et al. [5] demonstrated that Ang II was cleaved more efficiently by ACE2 to Ang-(1-7) [kcat/K(m) of 2.2 x 106 M-1 xs-1]. The conversion of Ang II into Ang-(1-7) shows a 500-fold higher efficiency compared to the hydrolysis of Ang I into Ang-(1-9).[6] Comparable kinetics are exhibited by two other substrates, dynorphin A and apelin-13.[6] The positioning of ACE2 as a critical enzymatic node for Ang II processing parallels that of the ACE node that converts Ang I into Ang II. In this respect, we have called attention to the possibility that the fate of angiotensin peptide formation and actions may be in part regulated at these sites through a positive feed forward loop, whereas ACE2 regulates the proportion of Ang II that is metabolized into Ang-(1-7).[4]

ACE2 Genetic Linkage to Hypertension

Early studies of genetic linkage of ACE2 with experimental models of hypertension and knockouts suggested that hypertension may be associated with reduced ACE2 gene expression and protein.[3,4,7] Genotyping for single nucleotide polymorphisms (SNP) has not shed definitive insight into whether ACE2 is a marker for a predisposition to hypertension. Negative results have been reported by Benjafield et al. [8] in essential hypertensive patients, whereas the ACE2 T allele was found to confer a 1.6-fold risk for hypertension in women [9] and in essential hypertensives in northern Han Chinese.[10] Similar association of the ACE2 gene with hypertension was recorded in another study of Chinese hypertensives.[11] In type 1 diabetic nephropathy, ACE2 polymorphisms were not associated with the disease.[12] However, genetic variants in the ACE2 gene were associated with left ventricular mass, higher septal wall thickness, and left ventricular hypertrophy in hemizygous men.[13] A protective role for ACE2 in prehypertension has been reported by Keidar et al. [14], who determined ACE2 activity in monocyte-derived macrophages isolated from blood samples of normotensives, prehypertensives, and untreated hypertensive male patients.

Role of ACE2 in Cardiovascular Regulation

The positioning of ACE2 as a critical regulator of the conversion of Ang II into Ang-(1-7) influences the local tissue actions of what has been termed the ACE2/Ang-(1-7)/mas-receptor axis.[15] Early studies showing that targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart [3] have been followed by the demonstration that transduction with lenti-mACE2 in the rat resulted in significant attenuation of cardiac hypertrophy and myocardial fibrosis induced by angiotensin II infusion.[16] Antihypertrophic actions of ACE2 are related to increased cardiac Ang-(1-7) as the administration of the peptide induces an antiproliferative response in myocytes in culture that is abolished by blockade of the mas receptor.[17] Studies documenting that the cardiac ACE2 transcript are upregulated in rats by chronic administration of ACE inhibitors or angiotensin receptor blockers suggest that ACE2 is negatively regulated by the tissue concentration of Ang II. This effect was first demonstrated in rats with combined myocardial infarction and losartan treatment [18] and has been confirmed in experiments in normal and hypertensive models of hypertension.[19,20]

ACE2 may have an important role in regulating the action of angiotensin peptides in the renal circulation [21] as it converts Ang II into Ang-(1-7).[22] The enzyme, primarily localized to glomerular and tubular epithelial cells [23], exhibits decreased activity in hypertensive rats; ACE2 expression is also downregulated in the kidneys of diabetic and pregnant rats.[24] Interestingly, ACE2 mutant mice develop late-onset glomerulonephritis resembling diabetic nephropathy.[25] In addition, chronic pharmacologic ACE2 inhibition worsens glomerular injury in streptozotocin-induced diabetic mice in association with increased ACE expression.[26] Since Ang-(1-7) inhibits Ang II-stimulated MAPK phosphorylation in proximal tubular cells [27], ACE2 could thereby serve a protective role by counteracting the effects of locally generated Ang II.


Beneficial actions of Ang-(1-7) against pathophysiologic processes such as cardiac arrhythmia, heart failure, hypertension, renal disease, and preeclampsia [28] have demonstrated the importance of other peptides in the RAS. The functional characterization of ACE2 has provided the regulatory step in determining the ratio of vasoconstrictor and vasodilator effects modulating the tissue function of Ang II and Ang-(1-7).[29] While more research is needed to determine the cellular and signaling mechanisms that regulate the balance between the pressor and proliferative ACE/Ang II/AT1 receptor and the opposing axis constituted by the ACE2/Ang-(1-7)/mas receptor, it is clear that identification of these novel regulatory mechanisms has enhanced our understanding of the system and unveiled new therapeutic opportunities to reduce the pathologic actions of Ang II in cardiovascular disease.


  1. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87(5):E1E9.
  2. Turner AJ, Tipnis SR, Guy JL, et al. ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors. Can J Physiol Pharmacol 2002;80(4):346353.
  3. Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002;417(6891):822828.
  4. 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(6):H2281H2290.
  5. Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004;383(Pt 1):4551.
  6. Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002;277(17):1483814843.
  7. Gurley SB, Allred A, Le TH, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006;116(8):22182225.
  8. Benjafield AV, Wang WY, Morris BJ. No association of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension. Am J Hypertens 2004;17(7):624628.
  9. Fan X, Wang Y, Sun K, et al. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women. Clin Pharmacol Ther 2007;82(2):187196.
  10. Huang W, Yang W, Wang Y, et al. Association study of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms and essential hypertension in northern Han Chinese. J Hum Hypertens 2006;20(12):968971.
  11. Liu TB, Shang HP, Zhang KX, et al. [Association of angiotensin I converting enzyme 2 gene polymorphism with essential hypertension in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005;22(5):569571.
  12. Frojdo S, Sjolind L, Parkkonen M, et al. Polymorphisms in the gene encoding angiotensin I converting enzyme 2 and diabetic nephropathy. Diabetologia 2005;48(11):22782281.
  13. Lieb W, Graf J, Gotz A, et al. Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy. J Mol Med 2006;84(1):8896.
  14. Keidar S, Strizevsky A, Raz A, Gamliel-Lazarovich A. ACE2 activity is increased in monocyte-derived macrophages from prehypertensive subjects. Nephrol Dial Transplant 2007;22(2):597601.
  15. Ferrario CM. Angiotensin-converting enzyme 2 and angiotensin-(1-7): an evolving story in cardiovascular regulation. Hypertension 2006;47(3):515521.
  16. Huentelman MJ, Grobe JL, Vazquez J, et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol 2005;90(5):783790.
  17. 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(4):H1560H1566.
  18. Ishiyama Y, Gallagher PE, Averill DB, et al. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004;43(5):970976.
  19. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111(20):26052610.
  20. Jessup JA, Gallagher PE, Averill DB, et al. Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. Am J Physiol Heart Circ Physiol 2006;291(5):H2166H2172.
  21. Ferrario CM, Jessup J, Gallagher PE, et al. Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors. Kidney Int 2005;68(5):21892196.
  22. Shaltout HA, Westwood BM, Averill DB, et al. Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol 2007;292(1):F82F91.
  23. Lely AT, Hamming I, van GH, Navis GJ. Renal ACE2 expression in human kidney disease. J Pathol 2004;204(5):587593.
  24. Danilczyk U, Penninger JM. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 2006;98(4):463471.
  25. Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol 2006;168(6):18081820.
  26. Soler MJ, Wysocki J, Ye M, et al. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int 2007;72(5):614623.
  27. Su Z, Zimpelmann J, Burns KD. Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int 2006;69(12):22122218.
  28. Brosnihan KB, Neves LA, Chappell MC. Does the angiotensin-converting enzyme (ACE)/ACE2 balance contribute to the fate of angiotensin peptides in programmed hypertension? Hypertension 2005;46(5):10971099.
  29. Trask AJ, Ferrario CM. Angiotensin-(1-7): pharmacology and new perspectives in cardiovascular treatments. Cardiovasc Drug Rev 2007;25(2):162174.

-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association. --