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Loss of the Mitochondrial Sodium/Calcium Exchanger in the Adult Heart Causes Sudden Death and Overexpression Protects Against Heart Failure
Author(s) -
Luongo Timothy S,
Nwokedi Mary,
Lambert Jonathan P,
Kolmetzky Devin,
Gao Erhe,
Carpenter April C.,
Song Jianliang,
Chen Xiongwen,
Patel Vickas V,
Madesh Muniswamy,
Molkentin Jeffery D,
Elrod John W
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.735.2
Subject(s) - heart failure , sodium calcium exchanger , calcium , programmed cell death , microbiology and biotechnology , mitochondrion , calcium metabolism , chemistry , apoptosis , medicine , biology , biochemistry
Mitochondrial calcium ( m Ca 2+ ) signaling is critical for both energy production and the activation of cell death pathways. Further, metabolic derangement and gradual cell dropout are mechanistically implicated as significant contributors 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 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 cardiomyocyte‐specific Cre mouse to delete mNCX in the adult heart (mNCX‐cKO). Biophysical study of cardiomyocytes isolated from mNCX‐cKO mice revealed a significant reduction in m Ca 2+ efflux rate and m Ca 2+ uptake capacity. Tamoxifen‐induced ablation of mNCX resulted in sudden death with most mice dying the first week after cre‐mediated deletion ( Figure 1). Echocardiographic evaluation of mNCX‐cKO hearts 3d post‐tamox revealed significant left ventricular (LV) remodeling characterized by significant dilation and a substantial decrease in function. Implantation of radiotelemeters revealed severe cardiac arrhythmias in mNCX‐cKO mice prior to sinus arrest. In addition, mNCX‐cKO hearts exhibited increased reactive oxygen species generation when assessed by DHE imaging of live tissue and mitoSOX Red imaging in isolated adult cardiomyocytes. Using an Evan's blue dye exclusion technique, we found that mNCX‐cKO hearts displayed significant sarcolemmal rupture, indicative of cellular necrosis. Next, we generated a conditional, cardiac‐specific mNCX overexpression mouse model (mNCX‐Tg) to evaluate if increasing m Ca 2+ efflux would alter the progression of HF. mNCX‐Tg and controls were subjected to in vivo 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 (MI %FS, Figure 2). For the first time, we show that mNCX is essential for maintenance of the m Ca 2+ microdomain in cardiomyocytes and that mNCX represents a novel therapeutic target in HF. Support or Funding Information National Institutes of Health: NIH/NHLBI (HL123966) American Heart Association: SDG (14SDG18910041) 12