title: Insights into the activation and inhibition of angiotensin II type 1 receptor in the mechanically loaded heart.
abstract: In the heart, mechanical load is a crucial regulator of myocardial structure and function; however, mechanical overload is a pathogenesis or comorbidity existing in a variety of heart diseases, such as hypertension, aortic regurgitation and myocardial infarction. Mechanical overload can be generally differentiated into 2 types, pressure overload (PO) and volume overload (VO), causing concentric and eccentric cardiac hypertrophy, respectively. The angiotensin II (AngII) type 1 receptor (AT1-R) is a 7 transmembrane G protein-coupled receptor that plays a critical role in load-induced cardiac hypertrophy. Early studies revealed the involvement of autocrine/paracrine mechanisms through stretch-induced release of AngII. Recent conceptually inspiring studies unraveled that the AT1-R could be also directly activated by mechanical stress. The activated AT1-R initiates intricate intracellular signaling pathways through G protein-dependent and G protein-independent mechanisms. AT1-R blocker (ARB) antagonizes the activation of AT1-R to regress cardiac remodeling. Some ARBs show properties of inverse agonism and arrestin-biased agonism at the AT1-R, which are potential therapeutic targets for the treatment of load-induced cardiac hypertrophy. This review summarizes the progress in the understanding of ligand- and mechanical stress-dependent activation of AT1-R, highlights recent data that investigate the role of AT1-R in the differentiation of PO- and VO-induced cardiac hypertrophy, and discusses the clinical relevance of inverse agonism and biased agonism of AT1-R ligands.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Jieyun
authors.initials: J
authors.lastname: You
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D019393:Arrestin / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019393:Arrestin; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II