Novel mechanism and role of angiotensin II induced vascular endothelial injury in hypertensive diastolic heart failure.
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.


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.
Yamamoto
Eiichiro
E
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Kataoka
Keiichiro
K
Shintaku
Haruo
H
Yamashita
Takuro
T
Tokutomi
Yoshiko
Y
Dong
Yi-Fei
YF
Matsuba
Shinji
S
Ichijo
Hidenori
H
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054144:Heart Failure, Diastolic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D014664:Vasodilation
D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D017311:Amlodipine; D001708:Biopterins; D006830:Hydralazine; D000068756:Valsartan; C056165:acetovanillone; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; D048848:MAP Kinase Kinase Kinase 5; C003402:sapropterin; D014633:Valine