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 Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ⅲ endothelium Ⅲ heart failure Ⅲ nitric oxide Ⅲ signal transduction S alt-sensitive hypertensive patients are more prone to cardiovascular diseases than their salt-insensitive counterparts. 1,2 Therefore, it is a clinically important issue to determine the mechanism and the therapeutic strategy of cardiovascular diseases in salt-sensitive hypertension. Vascular endothelial function plays a key role in the pathophysiology 3,4 and the prognosis 5-7 of cardiovascular diseases, including atherosclerosis, ischemic heart disease, and heart failure. However, the detailed molecular mechanism and the pathological significance of vascular endothelial dysfunction in salt-sensitive hypertension are unknown.Apoptosis signal-regulating kinase 1 (ASK1), a mitogenactivated protein kinase kinase kinase, has been identified as a proapoptotic signaling molecule. 8 -11 ASK1 is activated in response to a variety of stress stimuli, such as reactive oxygen species (ROS), angiotensin II (AII), or cytokines, etc. Accumulating in vitro evidence indicates that ASK1 participates in not only apoptosis but also various cellular responses, including cell differentiation and growth, or gene expression. Previously, we have shown that ASK1 is responsible for cardiac hypertrophy and fibrosis, 12 vascular intimal hyperplasia, 13 and ischemia-induced angiogenesis. 14 Furthermore, other investigators have also reported that ASK1 is implicated in cardiac myocyte death and remodeling induced by ischemia. 15,16 However, the role of ASK1 in vascular endotheli...