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(Hypertension. 2009;54:365.)
© 2009 American Heart Association, Inc.

Original Articles

Prevention of Pulmonary Hypertension by Angiotensin-Converting Enzyme 2 Gene Transfer

Yoriko Yamazato; Anderson J. Ferreira; Kwon-Ho Hong; Srinivas Sriramula; Joseph Francis; Masanobu Yamazato; Lihui Yuan; Chastity N. Bradford; Vinayak Shenoy; Suk P. Oh; Michael J. Katovich; Mohan K. Raizada

From the Department of Physiology and Functional Genomics, College of Medicine and McKnight Brain Institute (Y.Y., A.J.F., K.-H.H., M.Y., L.Y., C.N.B., S.P.O., M.K.R.), and Department of Pharmacodynamic, College of Pharmacy (V.S., M.J.K.), University of Florida, Gainesville, Fla; Department of Morphology (A.J.F.), Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Comparative Biomedical Sciences (S.S., J.F.), School of Veterinary Medicine, Louisiana State University, Baton Rouge, La.

Correspondence to Mohan K. Raizada, Department of Physiology and Functional Genomics, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610-0274. E-mail mraizada{at}phys.med.ufl.edu

In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25±1 mm Hg; MCT: 44±5 mm Hg; MCT+ACE2: 26±1 mm Hg; n=6; P<0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25±0.01; MCT: 0.31±0.01; MCT+ACE2: 0.26±0.01; n=8; P<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the angiotensin II type 2 receptor:angiotensin II type 1 receptor mRNA ratio. Also, pulmonary hypertension–induced increases in proinflammatory cytokines were significantly attenuated by lentiviral vector–containing ACE2 treatment. Furthermore, ACE2 gene transfer in mice after 6 weeks of MCT treatment resulted in a significant reversal of right ventricular systolic pressure. These observations demonstrate that ACE2 overexpression prevents and reverses right ventricular systolic pressure and associated pathophysiology in MCT-induced pulmonary hypertension by a mechanism involving a shift from the vasoconstrictive, proliferative, and fibrotic axes to the vasoprotective axis of the renin-angiotensin system and inhibition of proinflammatory cytokines.

Key Words: cardiovascular diseases • gene therapy • hypertension • pulmonary • lung • remodeling

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