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Reduced sarco/endoplasmic reticulum Ca(2+) uptake activity can account for the reduced response to NO, but not sodium

T Adachi1, R Matsui, R M Weisbrod

  • 1Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University Medical Center, Boston, MA, USA.

Circulation
|August 29, 2001
PubMed

Insights

Hypercholesterolemia impairs nitric oxide (NO) relaxation by reducing sarco/endoplasmic reticulum calcium ATPase (SERCA) function. This study reveals SERCA

Area of Science:

  • Vascular Biology
  • Cardiovascular Physiology
  • Smooth Muscle Pharmacology

Background:

  • Hypercholesterolemia (HC) impairs endothelium-dependent relaxation, but the direct effect on smooth muscle response to nitric oxide (NO) is unclear.
  • NO-mediated relaxation involves both cGMP-dependent and -independent pathways, including calcium (Ca2+) handling by sarco/endoplasmic reticulum calcium ATPase (SERCA).

Purpose of the Study:

  • To investigate the roles of cGMP and SERCA in the impaired smooth muscle response to NO and sodium nitroprusside (SNP) in hypercholesterolemic (HC) rabbit aorta.

Main Methods:

  • Used a guanylyl cyclase inhibitor and a SERCA inhibitor (cyclopiazonic acid, CPA) to assess relaxation mechanisms.
  • Measured SERCA activity via 45Ca2+ uptake and SERCA2 protein expression in normal and HC rabbit aorta.

Main Results:

  • SNP-induced relaxation was abolished by the guanylyl cyclase inhibitor, while NO-induced relaxation was only partially inhibited, with residual relaxation blocked by CPA.
  • CPA abolished residual NO-induced relaxation in both normal and HC aorta, but did not affect SNP-induced relaxation.
  • SERCA activity was significantly decreased in HC aorta, despite unchanged SERCA2 protein levels.

Conclusions:

  • NO-induced relaxation, unlike SNP-induced relaxation, is partially mediated by cGMP-independent Ca2+ uptake into the sarco/endoplasmic reticulum.
  • Reduced SERCA pump function in hypercholesterolemia contributes to the impaired vascular smooth muscle response to NO.
Abstract

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