Modulation of myocardial sarcoplasmic reticulum Ca(++)-ATPase in cardiac hypertrophy by angiotensin converting enzyme?

Abstract

Myocardial hypertrophy in response to hemodynamic overload is an established risk factor for cardiovascular morbidity and mortality. Partially, this may be due to alterations in cardiac gene expression, resulting in a more fetal-like myocyte phenotype with a fragile Ca(++)-homeostasis. Depressed expression of the sarcoplasmic reticulum Ca(++)-ATPase is the hallmark of this overload phenotype, contributing to prolonged cytosolic Ca(++)-transients, disturbed diastolic relaxation, altered force-frequency relation, and probably, electrophysiologic instability with susceptibility to malignant arrhythmias. Since angiotensin II is a growth-promoting factor in several cellular systems, the local formation of angiotensin II within the myocardium might contribute to the trophic response and the phenotype shift of overloaded myocardium. Several observations are consistent with this hypothesis: the cardiac expression of ACE and angiotensinogen is enhanced in experimental myocardial overload and in human endstage congestive heart failure; prolonged observations of experimental cardiac overload with hypertrophy-induced putative normalisation of myocardial systolic wall stress demonstrated a renormalization of ventricular tissue ACE activity and of ventricular sarcoplasmic Ca(++)-ATPase expression and activity; normalizing ventricular tissue ACE activity in experimental cardiac overload by chronic nonhypotensive ACE inhibitor therapy caused a parallel partial normalization of hypertrophy and underexpression of sarcoplasmic CA(++)-ATPase. This partial normalization of myocyte Ca(++)-homeostasis in overload hypertrophy by non-hypotensive chronic ACE-inhibition is attenuated by concomitant chronic application of bradykinin-2 receptor blockade, indicating an involvement of altered bradykinin metabolism in the phenotype modulation due to chronic ACE inhibition. While these observations are consistent with a direct influence of local ACE activity on the sarcoplasmic reticulum, the cell type contributing to the enhanced ACE expression in overload and the specific mechanism of this influence are unknown.