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. CONCLUSIONS: 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.
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 hypertensiverats (DSrats). Valsartan improved vascular endothelial dysfunction of DSrats 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 DSrats. 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 DSrats with established diastolic heart failure. CONCLUSIONS: 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.
Authors: Gad A Silberman; Tai-Hwang M Fan; Hong Liu; Zhe Jiao; Hong D Xiao; Joshua D Lovelock; Beth M Boulden; Julian Widder; Scott Fredd; Kenneth E Bernstein; Beata M Wolska; Sergey Dikalov; David G Harrison; Samuel C Dudley Journal: Circulation Date: 2010-01-18 Impact factor: 29.690
Authors: Y F Dong; L Liu; K Kataoka; T Nakamura; M Fukuda; Y Tokutomi; H Nako; H Ogawa; S Kim-Mitsuyama Journal: Diabetologia Date: 2009-11-06 Impact factor: 10.122
Authors: E M Seymour; Andrew A M Singer; Maurice R Bennink; Rushi V Parikh; Ara Kirakosyan; Peter B Kaufman; Steven F Bolling Journal: J Gerontol A Biol Sci Med Sci Date: 2008-10 Impact factor: 6.053
Authors: Hari K Parthasarathy; Burkert Pieske; Marianne Weisskopf; Chris D Andrews; Patrick Brunel; Allan D Struthers; Thomas M MacDonald Journal: Eur J Heart Fail Date: 2009-10 Impact factor: 15.534