Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy

Tatyana A. Vetter, Preethy Parthiban, Jackie A. Stevens, Xavier S. Revelo, Mark J. Kohr, De Wayne Townsend

Research output: Contribution to journalArticlepeer-review

Abstract

Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG−/− model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG−/− mice. Male β-SG−/− hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG−/− hearts. This protection of females was independent of ovarian hormones. Male β-SG−/− hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG−/− male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG−/− mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG−/− heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.

Original languageEnglish (US)
Pages (from-to)24-34
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume190
DOIs
StatePublished - May 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Ltd

Keywords

  • Angiotensin II type 1 receptor
  • Antioxidant
  • Dystrophic cardiomyopathy
  • Myocardial injury
  • S-nitrosylation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy'. Together they form a unique fingerprint.

Cite this