Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetophenones / pharmacology
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Acetophenones / therapeutic use
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Amlodipine / pharmacology
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Amlodipine / therapeutic use
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Angiotensin II / metabolism*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Angiotensin II Type 1 Receptor Blockers / therapeutic use
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Animals
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Antihypertensive Agents / pharmacology
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Antihypertensive Agents / therapeutic use
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Apoptosis* / drug effects
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Biopterins / analogs & derivatives
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Biopterins / pharmacology
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Biopterins / therapeutic use
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Blood Pressure
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Calcium Channel Blockers / pharmacology
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Calcium Channel Blockers / therapeutic use
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Disease Models, Animal
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / metabolism*
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Endothelium, Vascular / pathology
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Endothelium, Vascular / physiopathology
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Heart Failure, Diastolic / drug therapy
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Heart Failure, Diastolic / etiology
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Heart Failure, Diastolic / metabolism*
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Heart Failure, Diastolic / pathology
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Heart Failure, Diastolic / physiopathology
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Hydralazine / pharmacology
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Hydralazine / therapeutic use
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Hypertension / complications*
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Hypertension / drug therapy
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Hypertension / metabolism
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Hypertension / pathology
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Hypertension / physiopathology
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MAP Kinase Kinase Kinase 5 / antagonists & inhibitors
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NADPH Oxidases / metabolism
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Nitric Oxide Synthase Type III / metabolism*
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Rats
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Rats, Inbred Dahl
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Receptor, Angiotensin, Type 1 / drug effects
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Receptor, Angiotensin, Type 1 / metabolism*
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Signal Transduction
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Sodium Chloride, Dietary / administration & dosage
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Superoxides / metabolism
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Tetrazoles / pharmacology
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Tetrazoles / therapeutic use
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Time Factors
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Valine / analogs & derivatives
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Valine / pharmacology
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Valine / therapeutic use
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Valsartan
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Vasodilation
Substances
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Acetophenones
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Angiotensin II Type 1 Receptor Blockers
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Antihypertensive Agents
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Calcium Channel Blockers
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Receptor, Angiotensin, Type 1
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Sodium Chloride, Dietary
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Tetrazoles
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Superoxides
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Angiotensin II
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Amlodipine
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Biopterins
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Hydralazine
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Valsartan
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acetovanillone
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Nitric Oxide Synthase Type III
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Nos3 protein, rat
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NADPH Oxidases
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MAP Kinase Kinase Kinase 5
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sapropterin
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Valine