Abstract 93: Genetic Deletion of Slc8b1, the Mitochondrial Sodium/Calcium Exchanger, Causes Sudden Cardiac Death and Overexpression Protects Against Myocardial Infarction and Pressure-Overload Heart Failure

Abstract

Mitochondrial calcium ( m Ca 2+ ) signaling is critical for both energy production and the activation of cell death pathways in the heart. Further, m Ca 2+ overload is hypothesized to be a significant contributor to the development and progression of heart failure (HF). The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized to be the primary mechanism of m Ca 2+ efflux, but to date no study has genetically confirmed its identity or function in an in vivo system. To investigate the role of mNCX in HF, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1 (also known as NCLX) , and crossed them with a tamoxifen (tamox)-inducible cardiac-specific Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Cardiomyocytes isolated from mNCX-cKO mice displayed a significant reduction in m Ca 2+ efflux rate and Ca 2+ uptake capacity. Tamoxifen-induced ablation of mNCX resulted in sudden death with only 54% of mice surviving 8d post-tamoxifen treatment (Fig 1). Assessment of mNCX-cKO hearts 2d post-tamox revealed significant remodeling characterized by dilation and a decrease in %EF (Fig 2). Next, we generated a conditional, cardiac-specific mNCX overexpression mouse model (mNCX-Tg) to evaluate if increased m Ca 2+ efflux would alter the progression of HF. mNCX-Tg and controls were subjected to both myocardial infarction (LCA ligation) and pressure-overload induced HF (transverse aortic constriction). mNCX-Tg mice displayed preserved LV function, structure and a reduction in HF indices in both models. For the first time we show that mNCX is essential for m Ca 2+ efflux in cardiomyocytes and that mNCX represents a novel therapeutic target in HF.