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

Autor: Wexler AC; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Cardiology Section, Medical Service, William. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA., Dooge H; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Cardiology Section, Medical Service, William. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA., El-Meanawy S; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Cardiology Section, Medical Service, William. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA., Santos E; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Hacker T; Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Tewari A; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Alvarado FJ; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA., Ramratnam M; Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.; Cardiology Section, Medical Service, William. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology plus [J Mol Cell Cardiol Plus] 2024 Sep; Vol. 9.
DOI: 10.1016/j.jmccpl.2024.100088
Abstrakt: The small splice variant of the sulfonylurea receptor protein isoform 2 A (SUR2A-55) targets mitochondria and enhances mitoK ATP 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 (TG SUR2A-55 ) were examined by resting echocardiography and histopathology. In addition, hearts were subjected to ischemia reperfusion (IR) injury. Female TG SUR2A-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 TG SUR2A-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 TG SUR2A-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 TG SUR2A-55 hearts displayed reduced sensitivity to ATP and diazoxide suggestive of increased mitoK ATP activity. In conclusion, our data suggests that female TG SUR2A-55 mice are unable to tolerate a more active mitoK ATP 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 mitoK ATP subunits according to sex may elucidate different treatments for male and female patients.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Databáze: MEDLINE
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