on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.153692
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Submitted on March 29, 2007
Accepted on September 27, 2007
Novel Mechanism and Role of Angiotensin II–Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure
Eiichiro Yamamoto ;
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.
* To whom correspondence should be addressed. E-mail: kimmitsu{at}gpo.kumamoto-u.ac.
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.
Key words: angiotensin • endothelium • heart failure • nitric oxide • signal transduction
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