Enhanced coronary vasoconstriction in western diet‐induced obesity is associated with alterations in NHE1, SERCA2a and 3

Abstract

Cardiovascular disease (CVD) remains a major risk factor and cause of mortality in type 2 diabetes but, the effect of western diet (WD) on coronary artery vasoconstriction has not been well characterized. Therefore, the purpose of this study was to identify potential calcium (Ca2+) molecular mechanisms underlying alterations in coronary constriction in WD‐induced obesity. C57Bl/6J mice were fed a WD or control diet for 16wks. Coronary vascular function was assessed with wire myography and human coronary vascular smooth muscle cells (VSMC) were cultured. WD enhanced coronary constriction to the thromboxane analog U46619. This was associated with increased coronary VSMC expression of sodium‐hydrogen exchanger 1 (NHE1) and SERCA3 with decreased expression of SERCA2a. Oxidation of SERCA2a cysteine‐674, a signal for SERCA2a degradation, was increased in WD coronary VSMC. Exposure of cultured human coronary VSMC to hyperinsulinemic conditions elicited similar changes in SERCA2a, 3 and NHE1. This study suggests that enhanced thromboxane‐mediated coronary constriction in WD and insulin resistance/hyperinsulinemia may result from NHE1‐dependent changes in intracellular pH and/or impaired Ca2+ handling at the level of the SR. Supported by NIH HL107910, HL073101, and VA Merit Review 0018.