Abstract 1400: Reduced Cx43 Expression Reduces Scar Formation After Coronary Ligation

Abstract

Gap junctions mediate cell-to-cell electrical coupling required for synchronized cardiac contraction. They also serve as conduits for exchange of small signaling molecules. Reduction in connexin43 (Cx43), the major gap junction protein in ventricular tissue, likely underlies malignant arrhythmias in infarcted hearts. However, little is known about the role of reduced Cx43 expression in infarct healing. This study was performed to test the hypothesis that reduced expression of Cx43 influences cardiac fibroblast function and wound healing after myocardial infarction (MI). Methods: The left anterior coronary artery was ligated in wild-type (WTs) and Cx43-deficient (Cx43 +/− ) mice studied 6 d later. We quantified infarct size by Masson’s trichrome staining; cell proliferation by bromodeoxyuridine staining; matrix metallo-proteinase (MMP) activity in the noninfarcted, border and infarct regions (IZ) by zymography; myofibroblasts by α-smooth muscle actin (αSMA) immunostaining; and collagen deposition by Picrosirius red staining. Results: 6 d post-MI mean infarct size by trichrome staining was not different in Cx43 +/− (46±4%) vs WTs (46±5%). However, significant differences were observed in the Cx43 +/− infarcts. The area of unresorbed necrotic myocardium in the IZ was larger (p<0.01) in Cx43 +/− (40±11%, n=12) vs WTs (17±8%, n=6). Fibroblast proliferation in the IZ was increased (p<0.05) in Cx43 +/− (6.1±0.5%, n=4) vs WTs (4.1±0.7%, n=5), and activated MMP-2 was increased even more (p< 0.05) in the IZ of Cx43 +/− (40±6 relative density units, n=5) vs WTs (29±4 units, n=3) consistent with enhanced fibroblast proliferation. On the other hand, transformation to myofibroblasts in the IZ was diminished as reflected by reduced (p<0.01) αSMA-positive immunostaining in Cx43 +/− (32±16%, n=6) vs WTs (57±5%, n=12), and collagen deposition in the IZ was less (p<0.01) in Cx43 +/− (36±6%, n=6) vs WTs (50±13%, n=8) consistent with fewer myofibroblasts. Conclusion: Reduced Cx43 expression increases fibroblast proliferation and MMP activity, and reduces myofibro-blasts and collagen deposition indicating that remodeling of Cx43 can influence fibroblast function and delay scar formation and cardiac wound healing after MI.