The angiotensin II (AngII) type 1 (AT(1)) receptor is a seven transmembrane-spanning G-protein-coupled receptor, and the activation of AT(1) 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 AT(1) 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 AT(1) receptor. It is conceptually novel that AT(1) receptor directly mediates mechanical stress-induced cellular responses, and inverse-agonist activity emerges as an important pharmacological parameter for AT(1)-receptor blockers that determines their efficacy in preventing organ damage in cardiovascular diseases.
[1]Chiba Univ, Dept Cardiovasc Sci & Med, Grad Sch Med, Chuo Ku, Chiba 2608670, Japan.
[2]Chiba Univ, Div Cardiovasc Pathophysiol, Grad Sch Med, Chuo Ku, Chiba 2608670, Japan.
[3]Fudan Univ, Shanghai Inst Cardiovasc Dis, Zhongshan Hosp, Shanghai 200032, Peoples R China.
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