Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy

Man Liu, Lianzhi Gu, Matthew S. Sulkin, Hong Liu, Euy Myoung Jeong, Ian Greener, An Xie, Igor R. Efimov, Samuel C. Dudley

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Cardiomyopathy 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 (INa) 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 INa 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), INa 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 INa 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 INa. 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 INa. Reducing mitochondrial ROS by application of NAD+, mitoTEMPO, PKC inhibitors, or PKA activators, restored INa. NAD+ improved conduction velocity in human myopathic hearts.

Original languageEnglish (US)
Pages (from-to)25-34
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume54
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Sergey Dikalov (Emory University, Atlanta, GA) for the gift of mitoTEMPO. This 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 .

Keywords

  • Heart failure
  • Mitochondria
  • NAD
  • Oxidative stress
  • Sodium channel

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