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(Circulation Research. 2002;90:1114.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca²⁺-ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide–Induced Relaxation

Takeshi Adachi, Reiko Matsui, Shanqin Xu, Michael Kirber, Harold L. Lazar, Victor S. Sharov, Christian Schöneich, Richard A. Cohen

From the Vascular Biology Unit, Whitaker Cardiovascular Institute, Department of Medicine and Cardiothoracic Surgery, Boston University Medical Center (T.A., R.M., S.X., M.K., H.L.L., R.A.C.), Boston, Mass, and the Department of Pharmaceutical Chemistry, University of Kansas School of Pharmacy (V.S.S., C.S.), Lawrence, Kan.

Correspondence to Richard A. Cohen, MD, Director, Vascular Biology Unit, Boston University Medical Center X708, 650 Albany St, Boston, MA 02118-2393. E-mail racohen{at}medicine.bu.edu

Antioxidants improve endothelial function in hypercholesterolemia (HC); however, whether this includes improvement of the vascular smooth muscle response to NO is unknown. NO relaxes arteries, in part, by stimulating Ca²⁺ uptake via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) in aortic smooth muscle, and HC impairs SERCA function and the response to NO. HC induces oxidative stress, which could impair SERCA function. To study the effect of antioxidants, which are known to improve endothelium-dependent relaxation in HC, smooth muscle SERCA activity and NO-induced relaxation were studied in rabbits fed normal chow or a 0.5% cholesterol diet for 13 weeks. The antioxidant t-butylhydroxytoluene (BHT, 1%) was mixed with the HC diet in the last 3 weeks. HC impaired acetylcholine- and NO-induced relaxation, and these were restored by BHT. After inhibiting SERCA with thapsigargin, no difference existed in NO-induced relaxation among the three groups. Reduced aortic SERCA activity in HC was restored by BHT without changing SERCA protein expression. 3-Nitrotyrosine was notably increased in the media of the HC aorta, where it colocalized with SERCA. Tyrosine-nitrated SERCA protein was immunoprecipitated in the aortas of HC rabbits, where it was decreased by BHT, and it was also detected in the aortas of atherosclerotic humans. Thus, the antioxidant reverses impaired smooth muscle SERCA function in HC, and this is correlated with the improved relaxation to NO. These beneficial effects may depend on reducing the direct effects on SERCA of reactive oxygen species that are augmented in HC.

Key Words: t-butylhydroxytoluene • nitric oxide • sarco/endoplasmic reticulum Ca²⁺-ATPase • atherosclerosis • nitrotyrosine

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