In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy

Cardiac angiotensin-converting enzyme (ACE) may play an important role in r egulating cardiac hypertrophy. Angiotensin II (Ang II) stimulates cardiac h ypertrophy as well as the production of extracellular matrix. However, it i s still unclear whether Ang II exerts a direct effect on cardiac hypertroph y independent of its effect on blood pressure or the circulating renin-angi otensin system, Although ACE inhibitors and/or Ang II receptor antagonists have regressed cardiac hypertrophy, classic pharmacological experiments can not exclude the contribution of hemodynamics and the circulating renin-angi otensin 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 fu nction" approach to obtain local overexpression of cardiac ACE. Transfectio n of the human ACE vector into rat myocardium resulted in a significant inc rease 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 sign ificant increase in collagen content (P<0.01). This increase in cardiac hyp ertrophy was abolished by the administration of perindopril. Local transfec tion of the ACE vector into the heart did nor result in systemic effects su ch as increased blood pressure, heart rate, or serum ACE activity. In summa ry, we have demonstrated that increased autocrine/paracrine angiotensin can directly cause cardiac hypertrophy independent of systemic factors and hem odynamic effects, This approach has important potentials for defining the r ole of autocrine/paracrine substances in cardiovascular disease.