Objectives: The aim of this study was to investigate the effect of ischemia on cardiac Na+ channel (Nav1.5) and possible treatments in a mouse model of myocardial infarction (MI).
Methods: MI was induced in 12-week old C57BL/6 mice by coronary artery occlusion. Sham-operated mice were used as controls. Two weeks following surgery, MI mice were either given a mitochondria-targeted antioxidant, mitoTEMPO (0.7 mg/kg/day, intraperitoneally), or left untreated for two weeks. Cardiomyocytes isolated from the scar border of MI mice or from the left ventricular (LV) anterior wall of sham-operated mice were utilized for whole-cell patch clamp recording of Na+ currents (INa) and for measurements of mitochondrial reactive oxygen species (mitoROS) using flow cytometry. Nav1.5 protein expression levels were determined in the LV from MI and sham-operated mice. Echocardiography was performed 2- and 4-weeks following MI.
Results: The peak INa densities of the isolated LV cardiomyocytes were significantly lower (P<0.05) in MI (-14.3±1.4 pA/pF), compared to sham (-24.0±1.8 pA/pF). The mitoROS levels were elevated to 1.5±0.2 fold in MI mice (P<0.05). INa was increased (-19.4±0.8 pA/pF, P<0.05) and mitoROS was decreased to 1.2±0.2 fold (P<0.05) with mitoTEMPO treatment. The Nav1.5 channel protein level was not altered in the heart tissue of MI mice. There were no significant differences in echocardiography parameters between untreated and mitoTEMPO groups to explain the increase in INa.
Conclusions: Ischemic cardiomyopathy leads to downregulation of cardiac Nav1.5 currents and overproduction of mitochondrial ROS. The mitochondria-targeted antioxidant can mitigate these changes and may help reduce arrhythmic risk after myocardial infarction.