Journal
JOURNAL OF CARDIAC FAILURE
Volume 19, Issue 1, Pages 60-70Publisher
CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS
DOI: 10.1016/j.cardfail.2012.11.003
Keywords
Tetracycline-off; fura-2; in vivo catheterization; intracellular Ca2+ regulation
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Funding
- National Heart, Lung and Blood Institute [RO1-HL58672, RO1-HL74854, RO1-HL56205, RO1-HL61690, RO1-HL85503, PO1-HL-75443, PO1-HL-91799, PO1-HL91799]
- Pennsylvania Research Formulary Fund
- American Heart Association Scientist Development Grant [F64702]
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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. (J Cardiac Fail 2013;19:60-70)
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