Induced Overexpression of Na+ /Ca2+ Exchanger Does Not Aggravate Myocardial Dysfunction Induced by Transverse Aortic Constriction

Abstract Background Alterations in expression and activity of cardiac Na+ /Ca2+ exchanger (NCX1) have been implicated in the pathogenesis of heart failure. Methods and Results Using transgenic mice in which expression of rat NCX1 was induced at 5 weeks of age, we performed transverse aortic constriction (TAC) at 8 weeks and examined cardiac and myocyte function at 15–18 weeks after TAC (age 23–26 weeks). TAC induced left ventricular (LV) and myocyte hypertrophy and increased myocardial fibrosis in both wild-type (WT) and NCX1-overexpressed mice. NCX1 and phosphorylated ryanodine receptor expression was increased by TAC, whereas sarco(endo)plasmic reticulum Ca2+ -ATPase levels were decreased by TAC. Action potential duration was prolonged by TAC, but to a greater extent in NCX1 myocytes. Na+ /Ca2+ exchange current was similar between WT-TAC and WT-sham myocytes, but was higher in NCX1-TAC myocytes. Both myocyte contraction and [Ca2+ ]i transient amplitudes were reduced in WT-TAC myocytes, but restored to WT-sham levels in NCX1-TAC myocytes. Despite improvement in single myocyte contractility and Ca2+ dynamics, induced NCX1 overexpression in TAC animals did not ameliorate LV hypertrophy, increase ejection fraction, or enhance inotropic (maximal first derivative of LV pressure rise, +dP/dt) responses to isoproterenol. Conclusions In pressure-overload hypertrophy, induced overexpression of NCX1 corrected myocyte contractile and [Ca2+ ]i transient abnormalities but did not aggravate or improve myocardial dysfunction.