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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2569.)
© 2007 American Heart Association, Inc.

Vascular Biology

Novel Mechanism and Role of Angiotensin II–Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure

Eiichiro Yamamoto; Keiichiro Kataoka; Haruo Shintaku; Takuro Yamashita; Yoshiko Tokutomi; Yi-Fei Dong; Shinji Matsuba; Hidenori Ichijo; Hisao Ogawa; Shokei Kim-Mitsuyama

From the Department of Pharmacology and Molecular Therapeutics (E.Y., K.K., T.Y., Y.T., Y.-F.D., S.M., S.K.-M.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; the Department of Pediatrics (H.S.), Osaka City University Graduate School of Medicine, Osaka, Japan; the Laboratory of Cell Signaling (H.I.), Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan; and the Department of Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Correspondence to Shokei Kim-Mitsuyama, MD, PhD, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

Objective— The mechanism and role of angiotensin II–induced vascular endothelial injury is unclear. We examined the molecular mechanism of angiotensin (AII)-induced vascular endothelial injury and its significance for hypertensive diastolic heart failure.

Methods and Results— We compared the effect of valsartan and amlodipine on Dahl salt-sensitive hypertensive rats (DS rats). Valsartan improved vascular endothelial dysfunction of DS rats more than amlodipine, by inhibiting endothelial apoptosis and eNOS uncoupling more. Moreover, valsartan inhibited vascular apoptosis signal-regulating kinase 1 (ASK1) more than amlodipine. Thus, AT1 receptor contributed to vascular endothelial apoptosis, eNOS uncoupling, and ASK1 activation of DS rats. Using ASK1^–/– mice, we examined the causative role of ASK1 in endothelial apoptosis and eNOS uncoupling. AII infusion in wild-type mice markedly caused vascular endothelial apoptosis and eNOS uncoupling accompanied by vascular endothelial dysfunction, whereas these effects of AII were absent in ASK1^–/– mice. Therefore, ASK1 participated in AII-induced vascular endothelial apoptosis and eNOS uncoupling. Using tetrahydrobiopterin, we found that eNOS uncoupling was involved in vascular endothelial dysfunction in DS rats with established diastolic heart failure.

Conclusion— AII-induced vascular endothelial apoptosis and eNOS uncoupling were mediated by ASK1 and contributed to vascular injury in diastolic heart failure of salt-sensitive hypertension.

We examined the mechanism and significance of angiotensin II (AII)-induced vascular endothelial injury. AII-induced vascular endothelial apoptosis and eNOS uncoupling were mediated by apoptosis signal-regulating kinase 1 and contributed to the exacerbation of vascular injury of salt-sensitive hypertensive rats with diastolic heart failure.

Key Words: angiotensin • endothelium • heart failure • nitric oxide • signal transduction

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