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

  • Meijing WangEmail author
  • Kwynlyn Smith
  • Qing Yu
  • Caroline Miller
  • Kanhaiya Singh
  • Chandan K. Sen
Original Contribution


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.


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



This study was supported by the National Institutes of Health (NIH) R56 HL139967 (M.W.) and Showalter Trust Fund (M.W.). The authors thank Dr. Weinian Shou at IU School of Medicine for providing us doxycycline-inducible Tnnt2-Cre mice and for expert assistance in breeding Cx43-ic-KO mouse line. The authors thank Dr. Teresa A. Zimmers at IU School of Medicine for allowing access to the equipment for taking fluorescent images. The authors thank Dr. Subhadip Ghatak for contributions in editing the manuscript.

Compliance with ethical standards

Conflict of interest


Supplementary material

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Supplementary material 1 (PDF 561 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of SurgeryIndiana University School of MedicineIndianapolisUSA
  2. 2.Indiana Center for Regenerative Medicine and EngineeringIndiana University School of MedicineIndianapolisUSA
  3. 3.Electron Microscopy CenterIndiana University School of MedicineIndianapolisUSA

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