Journal of Molecular and Cellular Cardiology Plus (Sep 2024)

Cardiac overexpression of a mitochondrial SUR2A splice variant impairs cardiac function and worsens myocardial ischemia reperfusion injury in female mice

  • Allison C. Wexler,
  • Holly Dooge,
  • Sarah El-Meanawy,
  • Elizabeth Santos,
  • Timothy Hacker,
  • Aditya Tewari,
  • Francisco J. Alvarado,
  • Mohun Ramratnam

Journal volume & issue
Vol. 9
p. 100088

Abstract

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The small splice variant of the sulfonylurea receptor protein isoform 2 A (SUR2A-55) targets mitochondria and enhances mitoKATP activity. In male mice the overexpression of this protein promotes cardioprotection, reducing myocardial injury after an ischemic insult. However, it is unclear what impact SUR2A-55 overexpression has on the female myocardium. To investigate the impact of SU2R2A-55 on the female heart, mice with cardiac specific transgenic overexpression of SUR2A-55 (TGSUR2A-55) were examined by resting echocardiography and histopathology. In addition, hearts were subjected to ischemia reperfusion (IR) injury. Female TGSUR2A-55 mice had resting LV dysfunction and worse hemodynamic recovery with increased infarct size after IR injury. RNA-seq analysis found 227 differential expressed genes between WT and TGSUR2A-55 female mouse hearts that were enriched in pathways of cellular metabolism. This was in direct contrast to male mice that had only four differentially expressed genes. Female TGSUR2A-55 mice compared to female WT mice had reduced cardiomyocyte mitochondrial membrane potential without a change in electron transport chain protein expression. In addition, isolated mitochondria from female TGSUR2A-55 hearts displayed reduced sensitivity to ATP and diazoxide suggestive of increased mitoKATP activity. In conclusion, our data suggests that female TGSUR2A-55 mice are unable to tolerate a more active mitoKATP channel leading to LV dysfunction and worse response to IR injury. This is in direct contrast to our prior report showing cardioprotection in male mice overexpressing SUR2A-55 in heart. Future research directed at examining the expression and activity of mitoKATP subunits according to sex may elucidate different treatments for male and female patients.

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