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Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca(2+)-ATPase function and lowers tyrosine nitration

Takeshi Adachi1, Reiko Matsui, Shanqin Xu

  • 1Vascular Biology Unit, Whitaker Cardiovascular Institute, Department of Medicine and Cardiothoracic Surgery, Boston University Medical Center, Boston, Mass, USA.

Circulation Research
|June 1, 2002
PubMed

Insights

Antioxidants restore nitric oxide (NO) relaxation in hypercholesterolemia by improving vascular smooth muscle function. This study shows antioxidants reverse impaired sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity in hypercholesterolemia.

Area of Science:

  • Cardiovascular Biology
  • Vascular Physiology
  • Pharmacology

Background:

  • Hypercholesterolemia (HC) impairs endothelial function and vascular smooth muscle response to nitric oxide (NO).
  • Oxidative stress in HC may negatively affect sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) function, a key mediator of NO-induced relaxation.
  • The impact of antioxidants on NO-mediated vascular smooth muscle relaxation in HC is not well understood.

Purpose of the Study:

  • To investigate the effect of the antioxidant t-butylhydroxytoluene (BHT) on vascular smooth muscle SERCA activity and NO-induced relaxation in a rabbit model of hypercholesterolemia.
  • To determine if BHT can restore NO-mediated relaxation impaired by HC.
  • To explore the role of oxidative stress and SERCA function in HC-induced vascular dysfunction.

Main Methods:

  • Rabbits were fed a normal chow or a 0.5% cholesterol diet for 13 weeks. The antioxidant BHT (1%) was added to the HC diet during the final 3 weeks.
  • Vascular smooth muscle SERCA activity and NO-induced relaxation were measured in aortic tissues.
  • SERCA protein expression, 3-nitrotyrosine levels, and tyrosine-nitrated SERCA were assessed via immunoprecipitation.

Main Results:

  • Hypercholesterolemia impaired acetylcholine- and NO-induced relaxation, which were restored by BHT treatment.
  • Reduced aortic SERCA activity in HC rabbits was normalized by BHT without altering SERCA protein expression.
  • Increased 3-nitrotyrosine in HC aortas colocalized with SERCA, and tyrosine-nitrated SERCA was decreased by BHT, indicating reduced oxidative modification of SERCA.

Conclusions:

  • Antioxidant administration reverses impaired vascular smooth muscle SERCA function and restores NO-induced relaxation in hypercholesterolemia.
  • These beneficial effects are likely mediated by reducing the direct impact of reactive oxygen species on SERCA activity.
  • Targeting oxidative stress may be a viable strategy to improve vascular function in hypercholesterolemic conditions.

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