New: Angiotensin-Converting Enzyme 2

[David Feder]

Onset of Experimental Severe Cardiac Fibrosis Is Mediated by Overexpression of Angiotensin-Converting Enzyme 2
Rachel Masson; Stuart A. Nicklin; Margaret Anne Craig; Martin McBride; Kirsten Gilday; Paul Gregorevic; James M. Allen; Jeffrey S. Chamberlain; Godfrey Smith; Delyth Graham; Anna F. Dominiczak; Claudio Napoli; and Andrew H. Baker*

From the British Heart Foundation Glasgow Cardiovascular Research Centre (R.M., S.A.N., M.A.C., M.M., K.G., D.G., A.F.D., A.H.B.), Glasgow, United Kingdom; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centre (P.G., J.M.A., J.S.C.), University of Washington, Seattle; Faculty of Biological and Life Science (G.S.), University of Glasgow, Glasgow, United Kingdom; Sbarro Institute for Cancer Research and Molecular Medicine (C.N.), Temple University, Philadelphia, Pa; and the Department of General Pathology (C.N.), 1st School of Medicine, II University of Naples, Naples, Italy.

* To whom correspondence should be addressed. E-mail: [e-mail].

Abstract—Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis.

[David Feder]

The discovery of ACE2 can five a light about the drug that will be more helpful to prevent cardiac fibrosis in DMD: ACE inhibitor, losartan or both.



Angiotensin Converting Enzyme-2 (ACE2) and its Possible Roles in Hypertension, Diabetes and Cardiac Function

Abstract:

Angiotensin converting enzyme-2 (ACE2) is a recently described homologue of the vasoactive peptidase, angiotensin converting enzyme (ACE). Like ACE, ACE2 is an integral (type I) membrane zinc metallopeptidase, which exists as an ectoenzyme. ACE2 is less widely distributed than ACE in the body, being expressed at highest concentrations in the heart, kidney and testis. ACE2 also differs from ACE in its substrate specificity, functioning exclusively as a carboxypeptidase rather than a peptidyl dipeptidase. A key role for ACE2 appears to be emerging in the conversion of angiotensin II to angiotensin (1-7), allowing it to act as a counter-balance to the actions of ACE. ACE2 has been localised to the endothelial and epithelial cells of the heart and kidney where it may have a role at the cell surface in hydrolysing bioactive peptides such as angiotensin II present in the circulation. A role for ACE2 in the metabolism of other biologically active peptides also needs to be considered. ACE2 also serendipitously appears to act as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Studies using ace2^-/- mice, and other emerging studies in vivo and in vitro, have revealed that ACE2 has important functions in cardiac regulation and diabetes. Together with its role as a SARS receptor, ACE2 is therefore likely to be an important therapeutic target in a diverse range of disease states.