抄録
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. (Circ J 2014; 78: 1283–1289)
