title: Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension.
abstract: Angiotensin II (Ang-II) plays pivotal roles in the progression of left ventricular (LV) remodeling in diseased hearts; it remains to be elucidated how Ang-II links to degradation of the extracellular matrix (ECM). Using hypertensive Dahl salt-sensitive rats that show the distinctive transition from concentric LV hypertrophy to LV remodeling, we chronically treated them with an angiotensin type-1 receptor blocker (telmisartan 5 mg/kg/day, ARB group) or vehicle (0.5% CMC, CHF group). During the process of LV remodeling, we assessed, (1) in-vivo LV shape and function; (2) animal survival; (3) amounts of ECM in LV using a scanning electron microscope (SEM); (4) mRNA (by real time RT-PCR) and protein (by immunoblotting) levels in LV of NADPH oxidase, glutathione peroxidase-1 (GPX-1), and matrix metalloproteinase (MMP)-2, -9, and -13; (5) immunohistochemical staining of myocardial 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine; (6) nuclear factor kappa-B (NFkappaB) protein levels in the nuclear extract; and (7) endogenous activities of MMP-2 and -9 by an antibody capture method. Compared with CHF, ARB group showed an improvement of survival and preserved LV shape and function, and ECM density in SEM that was accompanied by decreases in oxidative stress-mediated protein degenerations, activities of GPX-1, NADPH oxidase, NFkappaB, and MMP-2, -9, and -13. Local activation of Ang-II in hypertrophic LV triggers MMP-mediated ECM degradation, namely LV remodeling, at least in part, through NADPH oxidase-induced oxidative stress and the subsequent NFkappaB activation.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takenaka
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Yoko
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D000804:Angiotensin II; D009247:NADH, NADPH Oxidoreductases; D020782:Matrix Metalloproteinases