ROLE OF ANGIOTENSIN-II AND PROSTAGLANDIN E(2) IN REGULATING CARDIAC FIBROBLAST COLLAGEN TURNOVER

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS effector hormone angiotensin II or prostaglandin E(2) (PGE(2)) directly modulates collagen synthesis or degradation in adult human cardiac fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [H-3]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [C-14]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of of angiotensin II or PGE(2) (10(-11)-10(-3) M), under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT(1) or AT(2)) receptor antagonists, respectively. Under these culture conditions, angiotensin II significantly stimulates collagen synthesis in a dose-dependent manner involving predominantly AT(1) receptors. In addition, angiotensin II inhibits MMP1 activity. In contrast, PGE(2) down-regulates collagen synthesis and increases collagen degradation. These findings suggest a direct interaction between the RAS effector hormone, angiotensin II, and cardiac fibroblasts in mediating myocardial fibrosis, whereas PGE(2), a key mediator of the bradykinin-prostaglandin system, appears to counteract the influence of RAS on myocardial collagen turnover.