title: Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II.
abstract: Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.
authors.affiliation: Department of Internal Medicine Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan. naikai@med.kurume0u.ac.jp
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mori
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tokuda
authors.forename: Narimasa
authors.initials: N
authors.lastname: Takayama
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tahara
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Takemiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kudo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sugi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fukui
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kuwahara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D005355:Fibrosis / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan