Remodeling of cardiac fibroblasts following myocardial infarction results in increased gap junction intercellular communication.
BACKGROUND
We have recently shown that native murine ventricular fibroblasts express both connexin43 (Cx43) and Cx45, and that the level of Cx43 expression influences intercellular coupling and cell proliferation. Relatively little is known, however, about how myocardial infarction (MI) influences expression of Cx43, or how altered Cx43 expression may affect fibroblast function post-MI. Fibroblasts are critical for infarct healing and post-infarct ventricular remodeling. They can couple electrically with cardiac myocytes and influence myocardial activation patterns. Thus, Cx43 remodeling and the level of intercellular communication in fibroblasts expressed in the infarcted heart were the subject of the present investigation.


METHODS
Fibroblasts were isolated from both infarct scar and remote, noninfarcted regions of murine hearts 6 d after coronary ligation. Expression levels of Cx43, α-smooth muscle actin and N-cadherin were quantified by immunoblotting. Gap junctional intercellular communication was quantified by Lucifer yellow dye transfer.


CONCLUSIONS
Fibroblasts isolated from infarcted hearts exhibited marked up-regulation of Cx43 protein expression and enhanced intercellular coupling. Exogenous administration of transforming growth factor-β (TGF-β) to fibroblast cultures from normal, non-operated hearts produced comparable up-regulation of Cx43, suggesting that increased intercellular communication between fibroblasts in infarct and peri-infarct regions may be secondary to activation of a TGF-β pathway. Unlike cardiac myocytes that down-regulate Cx43, presumably to limit intercellular transmission of biochemical mediators of ischemic injury, fibroblasts may up-regulate Cx43 to maintain electrical and metabolic coupling at a time when intercellular communication is compromised.
Zhang
Yan
Y
Department of Medicine (Cardiovascular Division and the Center for Cardiovascular Research), Washington University School of Medicine, St. Louis, MO, USA.
Kanter
Evelyn M
EM
Yamada
Kathryn A
KA
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020257:Ventricular Remodeling
D000199:Actins; D015820:Cadherins; C489083:Cdh2 protein, mouse; D018031:Connexin 43; D017630:Connexins; C543076:GJA1 protein, mouse; D053773:Transforming Growth Factor beta1; C082920:connexin 45