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dc.contributor.authorLiu, Man
dc.contributor.authorGu, Lianzhi
dc.contributor.authorSulkin, Matthew S.
dc.contributor.authorLiu, Hong
dc.contributor.authorJeong, Euy-Myoung
dc.contributor.authorGreener, Ian
dc.contributor.authorXie, An
dc.contributor.authorEfimov, Igor R.
dc.contributor.authorDudley, Samuel C.
dc.date.accessioned2013-12-03T23:02:51Z
dc.date.available2013-12-03T23:02:51Z
dc.date.issued2013-01
dc.identifier.bibliographicCitationLiu M, Gu L, Sulkin MS, Liu H, Jeong EM, Greener I, Xie A, Efimov IR, Dudley SC Jr. Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy. Journal of Molecular and Cellular Cardiology. 2013 Jan;54:25-34. doi: 10.1016/j.yjmcc.2012.10.011en_US
dc.identifier.issn0022-2828
dc.identifier.urihttp://hdl.handle.net/10027/10793
dc.descriptionNOTICE: This is the author’s version of a work that was accepted for publication in Journal of Molecular and Cellular Cardiology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Molecular and Cellular Cardiology, Vol 54, (2013) DOI: 10.1016/j.yjmcc.2012.10.011en_US
dc.description.abstractCardiomyopathy is associated with cardiac Na(+) channel downregulation that may contribute to arrhythmias. Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na(+) current (I(Na)) signaled by an increase in mitochondrial reactive oxygen species (ROS). In this study, we tested whether the NADH-mitochondria ROS pathway was involved in the reduction of I(Na) in a nonischemic cardiomyopathic model and correlated the findings with myopathic human hearts. Nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Sham operated mice were used as controls. After six weeks, heart tissue and ventricular myocytes isolated from mice were utilized for whole cell patch clamp recording, NADH/NAD(+) level measurements, and mitochondrial ROS monitoring with confocal microscopy. Human explanted hearts were studied using optical mapping. Compared to the sham mice, the arterial blood pressure was higher, the left ventricular volume was significantly enlarged (104.7±3.9 vs. 87.9±6.1μL, P<0.05), and the ejection fraction was reduced (37.1±1.8% vs. 49.4±3.7%, P<0.05) in DOCA mice. Both the whole cell and cytosolic NADH level were increased (279±70% and 123±2% of sham, respectively, P<0.01), I(Na) was decreased (60±10% of sham, P<0.01), and mitochondrial ROS overproduction was observed (2.9±0.3-fold of sham, P<0.01) in heart tissue and myocytes of myopathic mice vs. sham. Treatment of myocytes with NAD(+) (500μM), mitoTEMPO (10μM), chelerythrine (50μM), or forskolin (5μM) restored I(Na) back to the level of sham. Injection of NAD(+) (100mg/kg) or mitoTEMPO (0.7mg/kg) twice (at 24h and 1h before myocyte isolation) to animals also restored I(Na). All treatments simultaneously reduced mitochondrial ROS levels to that of controls. CD38 was found to transduce the extracellular NAD(+) signal. Correlating with the mouse model, failing human hearts showed a reduction in conduction velocity that improved with NAD(+). Nonischemic cardiomyopathy was associated with elevated NADH level, PKC activation, mitochondrial ROS overproduction, and a concomitant decrease in I(Na). Reducing mitochondrial ROS by application of NAD(+), mitoTEMPO, PKC inhibitors, or PKA activators, restored I(Na). NAD(+) improved conduction velocity in human myopathic hearts.en_US
dc.description.sponsorshipThis work was supported by NIH R01 HL085558, R01 HL072742, R01 HL106592, R01 HL104025, NIH R01 HL085369, T32 HL072742, and P01 HL058000 (SCD), and VA MERIT.en_US
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.titleMitochondrial Dysfunction Causing Cardiac Sodium Channel Downregulation in Cardiomyopathyen_US
dc.typeArticleen_US


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