Angiotensin II type 2 receptor is upregulated 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 (AT2-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 AT1-R and AT2-R was 59% and 41%, respectively. The expression of AT2-R was markedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold) levels compared with AMI or OMI. AT1-R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas in OMI and DCM hearts, AT1-R expression was significantly downregulated. AT1-R-mediated response in inositol phosphate production was significantly attenuated in LV homogenate from failing hearts compared with nonfailing hearts. AT2-R sites were highly localized in the interstitial region in either nonfailing or failing heart, whereas AT1-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 AT2-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) AT2-R expression is upregulated in failing hearts, and fibroblasts present in the interstitial regions are the major cell type responsible for its expression, (2) AT2-R present in the fibroblasts exerts an inhibitory effect on Ang II-induced mitogen signals, and (3) AT1-R in atrial and LV tissues was downregulated during chronic heart failure, and AT1-R-mediated functional biochemical responsiveness was decreased in the failing hearts. Thus, the expression level of AT2-R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expression and function of AT1-R and AT2-R are differentially regulated in failing human hearts.
Tsutsumi
Y
Y
Department of Medicine II, Kansai Medical University, Osaka, Japan.
Matsubara
H
H
Ohkubo
N
N
Mori
Y
Y
Nozawa
Y
Y
Murasawa
S
S
Kijima
K
K
Maruyama
K
K
Masaki
H
H
Moriguchi
Y
Y
Shibasaki
Y
Y
Kamihata
H
H
Inada
M
M
Iwasaka
T
T
D000328:Adult; D001344:Autopsy; D001706:Biopsy; D015152:Blotting, Northern; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D004719:Endomyocardial Fibrosis / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology*
D007295:Inositol Phosphates; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D017871:Calcium-Calmodulin-Dependent Protein Kinases