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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:428.)
© 2000 American Heart Association, Inc.

Vascular Biology

In Vivo Evidence of the Importance of Cardiac Angiotensin-Converting Enzyme in the Pathogenesis of Cardiac Hypertrophy

Jitsuo Higaki; Motokuni Aoki; Ryuichi Morishita; Iwao Kida; Yoshiaki Taniyama; Naruya Tomita; Kei Yamamoto; Atsushi Moriguchi; Yasufumi Kaneda; Toshio Ogihara

From the Department of Geriatric Medicine (J.H., M.A., R.M., I.K., Y.T., N.T., K.Y., A.M., T.O.) and the Division of Gene Therapy Science (R.M., Y.K.), Osaka University Medical School, Osaka, Japan.

Correspondence to Jitsuo Higaki, MD, PhD, Associate Professor, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita 565, Japan.

Abstract—Cardiac angiotensin-converting enzyme (ACE) may play an important role in regulating cardiac hypertrophy. Angiotensin II (Ang II) stimulates cardiac hypertrophy as well as the production of extracellular matrix. However, it is still unclear whether Ang II exerts a direct effect on cardiac hypertrophy independent of its effect on blood pressure or the circulating renin-angiotensin system. Although ACE inhibitors and/or Ang II receptor antagonists have regressed cardiac hypertrophy, classic pharmacological experiments cannot exclude the contribution of hemodynamics and the circulating renin-angiotensin system. In vivo gene transfer provides the opportunity of assessing the effects of increased cardiac angiotensin in the intact animal without circulating angiotensin or blood pressure. Therefore, we used a "gain of function" approach to obtain local overexpression of cardiac ACE. Transfection of the human ACE vector into rat myocardium resulted in a significant increase in cardiac ACE activity (P<0.01). More interestingly, morphometry at 2 weeks after transfection revealed a significant increase in the thickness and areas of cardiac myocytes in hearts transfected with the ACE vector (P<0.01). In addition, transfection of the ACE vector also resulted in a significant increase in collagen content (P<0.01). This increase in cardiac hypertrophy was abolished by the administration of perindopril. Local transfection of the ACE vector into the heart did not result in systemic effects such as increased blood pressure, heart rate, or serum ACE activity. In summary, we have demonstrated that increased autocrine/paracrine angiotensin can directly cause cardiac hypertrophy independent of systemic factors and hemodynamic effects. This approach has important potentials for defining the role of autocrine/paracrine substances in cardiovascular disease.

Key Words: remodeling • gene transfer • hypertrophy • angiotensin-converting enzyme • renin-angiotensin system

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