Induction of Angiotensin-Converting Enzyme and Activation of the Renin–Angiotensin System Contribute to 20-Hydroxyeicosatetraenoic Acid–Mediated Endothelial Dysfunction

OBJECTIVE—20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O2 production, and reducing NO bioavailability. Moreover, 20-HETE–dependent vascular dysfunction and hypertension are associated with upregulation of the renin–angiotensin system This study was undertaken to examine the contribution of renin–angiotensin system to 20-HETE actions in the vascular endothelium. METHODS AND RESULTS—In endothelial cells, 20-HETE induced angiotensin-converting enzyme (ACE) mRNA levels and increased ACE protein and activity by 2- to 3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20 HEDE). 20-HETE induced ACE expression was protein kinase C independent and epidermal growth factor receptor tyrosine kinase and IκB kinase β dependent. ACE short interfering RNA abolished 20-HETE–mediated inhibition of NO production and stimulation of O2 generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40%. 20-HETE–stimulated O2 production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE–mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. CONCLUSION—These results indicate that ACE and angiotensin II type 1 receptor activation contribute to 20-HETE–mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus, perpetuating an increase in vascular angiotensin which, together with 20-HETE, promotes vascular dysfunction.