Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-β signaling

Yan Zhang, Hongtao Wang, Attila Kovacs, Evelyn M. Kanter, Kathryn A. Yamada

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

In addition to mediating cell-to-cell electrical coupling, gap junctions are important in tissue repair, wound healing, and scar formation. The expression and distribution of connexin43 (Cx43), the major gap junction protein expressed in the heart, are altered substantially after myocardial infarction (MI); however, the effects of Cx43 remodeling on wound healing and the attendant ventricular dysfunction are incompletely understood. Cx43-deficient and wild-type mice were subjected to proximal ligation of the anterior descending coronary artery and followed for 6 days or 4 wk to test the hypothesis that reduced expression of Cx43 influences wound healing, fibrosis, and ventricular remodeling after MI. We quantified the progression of infarct healing by measuring neutrophil expression, collagen content, and myofibroblast expression. We found significantly reduced transformation of fibroblasts to myofibroblasts at 6 days and significantly reduced collagen deposition both in the infarct at 6 days and at 4 wk in the noninfarcted region of Cx43-deficient mice. As expected, transforming growth factor (TGF)-β, a profibrotic cytokine, was dramatically upregulated in MI hearts, but its phosphorylated comediator (pSmad) was significantly downregulated in the nuclei of Cx43-deficient hearts post-MI, suggesting that downstream signaling of TGF-β is diminished substantially in Cx43-deficient hearts. This diminution in profibrotic TGF-β signaling resulted in the attenuation of adverse structural remodeling as assessed by echocardiography. These findings suggest that efforts to enhance the expression of Cx43 to maintain intercellular coupling or reduce susceptibility to arrhythmias should be met with caution until the role of Cx43 in infarct healing is fully understood.

Original languageEnglish
Pages (from-to)H477-H487
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number2
DOIs
StatePublished - 2010

Keywords

  • Connexin43
  • Infarct remodeling
  • Myofibroblasts
  • Smads
  • Transforming growth factor-β

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