Pathophysiological roles of canstatin on myofibroblasts after myocardial infarction in rats

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Myofibroblasts play an important role during remodeling process after myocardial infarction through proliferation, migration, production and degradation of extracellular matrix (ECM) and contraction. Canstatin, a 24 kDa polypeptide, is cleaved from α2 chain of type IV collagen, which is a major component of basement membrane around cardiomyocytes. We examined the effects of canstatin on myofibroblasts isolated from the areas of myocardial infarction. Myocardial infarction model was made by ligating left anterior descending artery of Wistar rats. Two weeks after the operation, the cells were isolated by an explant method and identified as myofibroblasts with immunofluorescence staining. Cell counting assay was performed to examine cell proliferation. Boyden chamber assay was performed to examine cell migration. Expression and phosphorylation of proteins were detected by Western blotting. Collagen gel contraction assay was performed to measure cell contractility. Canstatin stimulated proliferation, secretion of matrix metalloproteinases, expression of cyclooxygenase (COX)-2, and inhibited collagen gel contraction in myofibroblasts. Canstatin increased Akt phosphorylation. LY294002, a phosphoinositide-3-kinase/Akt inhibitor, inhibited the canstatin-induced proliferation. NS-398, a COX-2 inhibitor, suppressed the inhibitory effect of canstatin on collagen gel contraction. Canstatin expression in areas of myocardial infarction 2 weeks after surgery decreased. We for the first time demonstrate that canstatin is an endogenous bioactive molecule regulating the various functions of myofibroblasts after myocardial infarction. The decrease of canstatin expression in the maturated areas of myocardial infarction might lead to stabilization of scar tissues perhaps in part through the reduction of proliferation and ECM degradation as well as the stimulation of contractility in myofibroblasts.

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