Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression

Abstract

Abstract—The expression pattern of angiotensin (Ang) II type 2 receptor (AT 2-R) in the remodeling process of human left ventricles (LVs) remains poorly defined. We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II. In autopsy 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 markedly 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 in OMI and DCM hearts, AT 1-R expression was significantly downregulated. AT 1-R–mediated response in inositol phosphate production was significantly attenuated in LV homogenate from failing hearts compared with nonfailing hearts. AT 2-R sites were highly localized in the interstitial region in either nonfailing or failing heart, whereas AT 1-R was evenly distributed over myocardium at lower densities. Mitogen-activated protein kinase (MAPK) activation by Ang II was significantly decreased in fibroblast compartment from the failing hearts, and pretreatment with AT 2-R antagonist caused an additional significant increase in Ang II–induced MAPK activity (36%). Cardiac hypertrophy suggested by atrial and brain natriuretic peptide levels was comparably increased in OMI and DCM, whereas accumulation of matrix proteins such as collagen type 1 and fibronectin was much more prominent in DCM than in OMI. These findings demonstrate that (1) AT 2-R expression is upregulated in failing hearts, and fibroblasts present in the interstitial regions are the major cell type responsible for its expression, (2) AT 2-R present in the fibroblasts exerts an inhibitory effect on Ang II–induced mitogen signals, and (3) AT 1-R in atrial and LV tissues was downregulated during chronic heart failure, and AT 1-R–mediated functional biochemical responsiveness was decreased in the failing hearts. Thus, the expression level of AT 2-R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expression and function of AT 1-R and AT 2-R are differentially regulated in failing human hearts.