RENIN-ANGIOTENSIN SYSTEM AND MYOCARDIAL COLLAGEN MATRIX - MODULATION OF CARDIAC FIBROBLAST FUNCTION BY ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONISM

Background Left ventricular hypertrophy is an adaptive process to incr eased loading of the left ventricle. This condition becomes pathologic with impaired myocardial function if the various tissue compartments of the myocardium (myocyte, interstitial and vascular compartments) ar e inhomogeneously altered, particularly if myocardial fibrosis occurs. In arterial hypertension, myocardial fibrosis is known to occur in as sociation with activated circulating or local renin-angiotensin system s and includes reactive perivascular and interstitial fibrosis in both the pressure-overloaded hypertrophied left ventricle and the normoten sive non-hypertrophied right ventricle. Therefore, it appears that hem odynamics are not primarily responsible for the adverse myocardial col lagen matrix remodeling in hypertensive heart disease. Accordingly, we studied the interaction between cultured adult rat cardiac fibroblast s, which express messenger (m)RNAs for types I and III collagens, the major fibrillar collagens in the heart, and angiotensin II (Ang II), t he effector homone of the renin-angiotensin system. Objectives Specifi cally, we sought to determine whether Ang II stimulates total collagen synthesis and the expression of type I collagen mRNA in cultured adul t rat cardiac fibroblasts, and to investigate the effects of Ang II on intracellular Ca2+ levels. Materials and methods Adult rat cardiac fi broblasts were cultured in Dulbecco's Modified Eagle's Medium + 10% fe tal calf serum and incubated for 24 h with Ang II with or without spec ific Ang II type 1 or type 2 receptor antagonists. Collagen synthesis was measured using a H-3-proline incorporation assay, and type I colla gen mRNA was determined using reverse-transcriptase polymerase chain r eaction. Intracellular Ca2+ transients were measured by fast fluoresce nce photometry using the fluorescent dye fura-2-ace-toxymethylester. R esults We found a 76% increase in type I collagen mRNA in cultured car diac fibroblasts after a 24-h incubation with Ang II, and this was abo lished by simultaneous incubation with the Ang II type 1 (AT(1))-recep tor antagonist candesartan. Likewise, total collagen synthesis was sti mulated by Ang II in a dose-dependent manner, and this stimulation was also counteracted by candesartan. Additionally, incubation with Ang I I resulted in a significant dose-dependent increase in intracellular C a2+ transients which was also abolished by treatment with candesartan. Conclusions Ang II stimulates collagen synthesis in cultured adult rat cardiac fibroblasts via AT(1) receptors, most likely using Ca2+ as a second messenger. These findings suggest a direct interaction between Ang II and cardiac fibroblasts in mediating myocardial fibrosis in art erial hypertension, leading to pathologic left ventricular hypertrophy with initially impaired diastolic and ultimately reduced systolic fun ction of the left ventricle. The AT(1)-receptor antagonist candesartan cilexetil, which is the prodrug of the active compound candesartan, m ay prove valuable in preventing or regressing myocardial fibrosis in h ypertensive heart disease. (C) Rapid Science Publishers.