title: Role of the renin-angiotensin system in cardiac hypertrophy.
abstract: Hypertrophy is an adaptive response of the heart to hemodynamic overload such as hypertension. However, it is generally accepted that cardiac hypertrophy is one of the most critical risk factors of heart disease. Therefore, for the treatment of hypertension it is important to understand the mechanism of cardiac hypertrophy and to establish effective pharmaceutical interventions. Mechanical stretch induced by hypertension is an initial factor leading to cardiac hypertrophy. In an in vivo study using spontaneously hypertensive rats, an angiotensin II type 1 receptor antagonist, TCV116, decreased left ventricular weight, left ventricular wall thickness, transverse myocyte diameter, relative amount of V3 myosin heavy chain, and interstitial fibrosis, whereas treatment with hydrolazine did not. In an in vitro study using cultured cardiomyocytes of neonatal rats, mechanical stretch activated second messengers, such as extracellular signal-regulated protein kinase (ERK), followed by increased protein synthesis. Additionally, in the stretch-conditioned medium, the levels of angiotensin II and endothelin-1 concentrations were increased. Moreover, the Na+/H+ exchanger activated by mechanical stretch modulated the hypertrophic responses of cardiomyocytes. To further elucidate whether angiotensin II is indispensable for mechanical stress-induced cardiac hypertrophy, mechanical stretch-induced ERK activation was examined in angiotensin II type 1a receptor knock-out mice. Although the addition of angiotensin II had no effects on the ERK activity in cardiomyocytes of angiotensin II type 1a receptor knockout mice, mechanical stretch induced a larger increase in the ERK activity in cardiac myocytes from these mice compared with cardiac myocytes of wild-type mice. These results suggest that mechanical stretch could induce hypertrophic responses in cardiac myocytes even in the absence of angiotensin II. The pathways leading to ERK activation differed between cell types. In cardiac fibroblasts, angiotensin II activated ERK via the G(beta)gamma subunit of Gi, Src, Shc, Grb2, and Ras, whereas Gq and protein kinase C were critical in cardiomyocytes.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.forename: I
authors.initials: I
authors.lastname: Komuro
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013777:Tetrazoles
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D017923:Sodium-Hydrogen Exchangers; D013777:Tetrazoles; D000804:Angiotensin II; D006830:Hydralazine; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C077793:candesartan cilexetil