RIGHT-VENTRICULAR ANGIOTENSIN-CONVERTING ENZYME-ACTIVITY AND EXPRESSION IS INCREASED DURING HYPOXIC PULMONARY-HYPERTENSION

Objective: To determine whether local cardiac angiotensin converting e nzyme (ACE) expression is upregulated during the development of hypoxi a-induced right ventricular hypertrophy. Methods: ACE activity was mea sured in membrane preparations from the right ventricle and left ventr icle plus septum in normoxic rats and animals exposed to chronic hypox ia for 8 and 14 days. Local cardiac ACE expression was studied by immu nohistochemistry using a monoclonal antibody to ACE (9B9). Results: In the normal rat heart, ACE expression was confined to vascular endothe lium, the valvular endocardium, and localized regions of parietal endo cardium. We found that the development of pulmonary hypertension and r ight ventricular hypertrophy were associated with 2.6- and 3.4-fold in creases in membrane-bound right ventricular ACE activity by 8 and 14 d ays of hypoxia, respectively. Right ventricular ACE activity was posit ively correlated with the degree of right ventricular hypertrophy (r = 0.83, P < 0.001). In contrast, left ventricular plus septal ACE activ ity was significantly reduced by approximately 40 and 60% by 8 and 14 days of hypoxia, respectively, compared to controls. In the right vent ricle of chronically hypoxic rats, immunohistochemistry demonstrated i ncreased ACE expression in areas of myocardial fibrosis. Interestingly , increased ACE expression was noted in the right ventricular epicardi um in chronically hypoxic rats. In the free wall of the left ventricle there was a significant reduction in the number of myocardial capilla ries which expressed ACE in chronically hypoxic rats. Conclusion: Chro nic hypoxia has a differential effect on left and right ventricular AC E activity and that the sites of altered ACE expression are highly loc alized. We speculate that locally increased right ventricular ACE acti vity and expression may play a role in the pathogenesis of right ventr icular hypertrophy secondary to hypoxic pulmonary hypertension.