A novel mechanism of mechanical stress-induced angiotensin II type 1-receptor activation without the involvement of angiotensin II.
The angiotensin II (AngII) type 1 (AT1) receptor is a seven transmembrane-spanning G-protein-coupled receptor, and the activation of AT1 receptor plays an important role in the development of load-induced cardiac hypertrophy. Locally generated AngII was believed to trigger cardiac hypertrophy by an autocrine or paracrine mechanism. However, we found that mechanical stress can activate AT1 receptor independently of AngII. Without the involvement of AngII, mechanical stress not only activates extracellular signal-regulated kinases in vitro, but also induces cardiac hypertrophy in vivo. All of these events are inhibited by candesartan as an inverse agonist for AT1 receptor. It is conceptually novel that AT1 receptor directly mediates mechanical stress-induced cellular responses, and inverse-agonist activity emerges as an important pharmacological parameter for AT1-receptor blockers that determines their efficacy in preventing organ damage in cardiovascular diseases.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Noritaka
N
Yasuda
Hiroshi
H
Akazawa
Yingjie
Y
Qin
Yunzeng
Y
Zou
Issei
I
Komuro
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology*; D054314:Drug Inverse Agonism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; C081643:candesartan