ANGIOTENSIN-II TYPE-2 RECEPTOR IS UP-REGULATED IN HUMAN HEART WITH INTERSTITIAL FIBROSIS, AND CARDIAC FIBROBLASTS ARE THE MAJOR CELL-TYPE FOR ITS EXPRESSION

The expression pattern of angiotensin (Ang) II type 2 receptor (AT(2)- R) in the remodeling process of human left ventricles (LVs) remains po orly defined. We analyzed its expression at protein, mRNA, and cellula r levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infa rction and idiopathic dilated cardiomyopathy (DCM) and also examined f unctional biochemical responses of failing hearts to Ang II. In autops y samples from the nonfailing heart group, the ratio of AT(1)-R and AT (2)-R was 59% and 41%, respectively. The expression of AT(2)-R was mar kedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold ) levels compared with AMI or OMI. AT(1)-R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas i n OMI and DCM hearts, AT(1)-R expression was significantly downregulat ed. AT(1)-R-mediated response in inositol phosphate production was sig nificantly attenuated in LV homogenate from failing hearts compared wi th nonfailing hearts. AT(2)-R sites were highly localized in the inter stitial region in either nonfailing or failing heart, whereas AT(1)-R was evenly distributed over myocardium at lower densities. Mitogen-act ivated protein kinase (MAPK) activation by Ang II was significantly de creased in fibroblast compartment from the failing hearts, and pretrea tment with AT(2)-R antagonist caused an additional significant increas e in Ang II-induced MAPK activity (36%). Cardiac hypertrophy suggested by atrial and brain natriuretic peptide levels was comparably increas ed in OMI and DCM, whereas accumulation of matrix proteins such as col lagen type I and fibronectin was much more prominent in DCM than in OM I. These findings demonstrate that (1) AT(2)-R expression is upregulat ed in failing hearts, and fibroblasts present in the interstitial regi ons are the major cell type responsible for its expression, (2) AT(2)- R present in the fibroblasts exerts an inhibitory effect on Ang II-ind uced mitogen signals, and (3) AT(1)-R in atrial and LV tissues was dow nregulated during chronic heart failure, and AT(1)-R-mediated function al biochemical responsiveness was decreased in the failing hearts. Thu s, the expression level of AT(2)-R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expres sion and function of AT(1)-R and AT(2)-R are differentially regulated in failing human hearts.