Mitochondrial connexin 43 in sex-dependent myocardial responses and estrogen-mediated cardiac protection following acute ischemia/reperfusion injury

Meijing Wang, Kwynlyn Smith, Qing Yu, Caroline Miller, Kanhaiya Singh, Chandan K. Sen

Research output: Contribution to journalArticle

Abstract

Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17β-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection.

Original languageEnglish (US)
Article number1
JournalBasic Research in Cardiology
Volume115
Issue number1
DOIs
StatePublished - Jan 1 2020

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Connexin 43
Reperfusion Injury
Estrogens
Cardiac Myocytes
Reperfusion
Myocardial Reperfusion
Mitochondria
Ischemia
Myocardial Ischemia
Phosphorylation
Warm Ischemia
Ischemic Preconditioning
Immunoelectron Microscopy
Doxycycline
Mitochondrial Membrane Potential
Immunoprecipitation
Superoxides
Sex Characteristics
Estrogen Receptors
Estradiol

Keywords

  • Cardiac dysfunction
  • Estrogen
  • Mitochondrial connexin 43
  • Myocardial ischemia reperfusion
  • Sex-based mitochondrial performance

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Mitochondrial connexin 43 in sex-dependent myocardial responses and estrogen-mediated cardiac protection following acute ischemia/reperfusion injury. / Wang, Meijing; Smith, Kwynlyn; Yu, Qing; Miller, Caroline; Singh, Kanhaiya; Sen, Chandan K.

In: Basic Research in Cardiology, Vol. 115, No. 1, 1, 01.01.2020.

Research output: Contribution to journalArticle

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