A novel mechanism of mechanical stress-induced hypertrophy.
Angiotensin II (AII) type 1 (AT1) receptor plays a critical role in load-induced cardiac hypertrophy. We have recently found a novel mechanism of mechanical stress-induced activation of the AT1 receptor, which is independent of AII. Mechanical stretch did not activate ERKs in HEK293 cells and COS7 cells which had no AT1 receptor, but when AT1 receptor was overexpressed in these cells, stretch activated ERKs, Galphaq and JAK2. An AT1 receptor blocker, candesartan, inhibited stretch-induced activation of ERKs in these cells. Stretch also activated ERKs in COS7 cells expressing AT1 mutant which did not bind AII and in cardiac myocytes prepared from angiotensinogen null mice. Stretch did not activate ERKs in COS7 cells which overexpressed ETA receptor and beta-adrenergic receptor. Pressure overload induced cardiac hypertrophy in angiotensinogen null mice as well as in wild-type mice, which was significantly inhibited by candesartan. These results suggest that mechanical stress activates AT1 receptor independently of AII, which is inhibited by an inverse agonist candesartan.
Akazawa
Hiroshi
H
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Zou
Yunzeng
Y
Komuro
Issei
I
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D019556:COS Cells; D006332:Cardiomegaly / Q000473:pathology*; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D048049:Extracellular Signal-Regulated MAP Kinases; C081643:candesartan