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(Hypertension. 2009;53:694.)
© 2009 American Heart Association, Inc.

Original Articles

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; 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.

Correspondence to Andrew H. Baker, BHF GCRC, University of Glasgow, 126 University Place, Glasgow, G12 8TA United Kingdom. E-mail ab11f{at}clinmed.gla.ac.uk

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.

Key Words: ACE2 • gene delivery • adeno-associated virus • hypertension • myocardium