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Attenuation of Angiotensin II Signaling Recouples eNOS and Inhibits Nonendothelial NOX Activity in Diabetic Mice

From the Division of Molecular Medicine, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California

Address correspondence and reprint requests to Hua "Linda" Cai, MD, PhD, Division of Molecular Medicine, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California Los Angeles, 650 Charles E. Young Dr. South, Suite BH550 CHS, Los Angeles, CA 90095. E-mail: hlcai{at}ucla.edu

Abbreviations: Ang II, angiotensin II; AT1R, Ang II receptor type 1; CMH, methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine; DETC, diethyldithiocarbamic acid; DHE, dihydroethidium; DHFR, dihydrofolate reductase; eNOS, endothelial nitric oxide synthase; ESR, electron spin resonance; H₄B, tetrahydrobiopterin; L-NAME, N-nitro-L-arginine methyl ester hydrochloride; NOX, NAD(P)H oxidase; ROS, reactive oxygen species; STZ, streptozotocin; VSMC, vascular smooth muscle cell

Angiotensin II (Ang II) levels are increased in patients with diabetes, but mechanisms underlying its contribution to diabetic vascular diseases are incompletely understood. We recently reported that in aortic endothelial cells, Ang II induces endothelial nitric oxide synthase (eNOS) uncoupling to produce superoxide (O₂·^–) rather than nitric oxide (NO·), upon loss of the tetrahydrobiopterin (H₄B) salvage enzyme dihydrofolate reductase (DHFR). Here, we found that streptozotocin-induced diabetic mice had a marked increase in aortic O₂·^– production, which was inhibited by N-nitro-L-arginine methyl ester hydrochloride, indicating uncoupling of eNOS. Ang II receptor type 1 blocker candesartan or ACE inhibitor captopril markedly attenuated eNOS-derived O₂·^– and hydrogen peroxide production while augmenting NO· bioavailability in diabetic aortas, implicating recoupling of eNOS. O₂·^– and NO· production were characteristically and quantitatively measured by electron spin resonance. DHFR expression was decreased in diabetic aortas but significantly restored by candesartan or captopril. Either also improved vascular H₄B content and endothelium-dependent vasorelaxation in diabetes. Rac1-dependent NAD(P)H oxidase (NOX) activity was more than doubled in the endothelium-denuded diabetic aortas but was attenuated by candesartan or captopril, indicating that NOX remains active in nonendothelial vascular tissues, although uncoupled eNOS is responsible for endothelial production of O₂·^–. These data demonstrate a novel role of Ang II in diabetic uncoupling of eNOS and that Ang II–targeted therapy improves endothelial function via the novel mechanism of recoupling eNOS. Dual effectiveness on uncoupled eNOS and NOX may explain the high efficacy of Ang II antagonists in restoring endothelial function.

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