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タイトル :Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: The critical role of ASK1 and VEGF
著者 :Nako, Hisato
Kataoka, Keiichiro
Koibuchi, Nobutaka
Dong, Yi-Fei
Toyama, Kensuke
Yamamoto, Eiichiro
Yasuda, Osamu
Ichijo, Hidenori
Ogawa, Hisao
Kim-Mitsuyama, Shokei
刊行年月日 :2012-2
収録雑誌名 :Hypertension Research
巻 :35
号 :2
開始ページ :194
終了ページ :200
要約(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.
URL :http://www.nature.com/hr/journal/v35/n2/abs/hr2011175a.html
収録種別 :雑誌掲載論文
ISSN :09169636
出版社(者) :Nature Publishing Group
URI :http://hdl.handle.net/2298/25964
このアイテムの引用には次の識別子を使用してください: http://hdl.handle.net/2298/25964