title: Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF.
abstract: This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Nako
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Dong
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D007150:Immunohistochemistry; D000077405:Irbesartan; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; D000804:Angiotensin II; D006830:Hydralazine; D048848:MAP Kinase Kinase Kinase 5; D000077405:Irbesartan; C001803:tempol