title: Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis.
abstract: Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day -7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-beta expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-beta and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1-mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.
authors.affiliation: Department of Internal Medicine III and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tokuda
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kuwahara
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kudo
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Takemiya
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Koga
authors.forename: Tomoka
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001011:Aorta; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure; D002465:Cell Movement / Q000187:drug effects; D003250:Constriction; D003331:Coronary Vessels / Q000473:pathology; D005355:Fibrosis; D006973:Hypertension / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C081643:candesartan