Insulin Ameliorates Collagen Remodeling After Myocardial Infarction

Cardiac fibroblasts (CFs), as the most prevalent cell type in the heart,play a key role in regulating normal myocardial function and in the adversemyocardial remodeling that occurs with hypertension, myocardial infarction(MI)，and are involved in the pathogenesis of heart failure. In cardiovasculardiseases CFs perform pivotal roles in myocardial remodeling characterized bycardiomyocyte death or hypertrophy, migration and proliferation of fibroblastsand changes in the synthesis and deposition of extracellular matrix (ECM).Our previous studies showed that insulin could reduce myocardial apoptoticdeath and improve cardiac function after acute myocardial infarction via thePI3K-Akt-eNOS survival signaling. However, the effect of insulin on collagenremodeling after MI and its underlying mechanisms remain unclear.AimsThe study was designed to investigate whether insulin treatment could ameliorate collagen remodeling after MI and to explore the underlyingmechanisms.MethodsAdult male rats were subjected to the ligation of anterior descendingcoronary artery and randomized to receive one of the following treatments:Sham, MI+Saline or MI+Insulin. Peri-farcted myocardial hydroxyprolineconcentration was measured with chemistry kit. Cardiac a-SMA expressionswere detected by western blot analysis. The ratios of myocardial collagen I/IIIwere measured with immunohistochemistry staining and western blot.Cultured neonatal rat cardiac fibroblasts were simulated by transforminggrowth factor (TGF-β10ng/mL) for24h, and cells were divided into blank(CF), control (CF+TGF-β) and insulin (CF+TGF-β+Insulin) groups. Cardiacfibroblasts were identified by DDR2immunofluorescence staining. Collagensynthesis was detected by a-SMA expression and the phosphorylation ofSmad2. ERK1/2, p38MAPK and JNK expression were measured with westernblot.ResultsInsulin significantly improved cardiac function by increasing leftventricular ejection fraction after ischemia. Cardiac collagen contents weredecreased post-MI as evidenced by reduced peri-farcted myocardialhydroxyproline concentration and a-SMA expression (P<0.05and P<0.01,respectively). Meanwhile, immunohistochemistry staining and western blotanalysis showed that the ratios of myocardial collagen I/III at1wk and4wkpost-MI were significantly higher than those in the sham hearts (P<0.05),while insulin treatment significantly reduced the ratios of collagen I/III compared with those in saline hearts1wk post-MI (P<0.05); however, therewere no differences in the ratios of collagen I/III4wk post-MI (P>0.05).Furthermore, insulin reduced TGF-β induced a-SMA expression (P<0.05) andthe phosphorylation of Smad2(P<0.05) in neonatal rat cardiac fibroblasts.Also, insulin reduced the phosphorylation of JNK in neonatal rat cardiacfibroblasts simulated by TGF-β.ConclusionInsulin ameliorates cardiac collagen remodeling in post-MI hearts,probably via reduced collagen contents and JNK phosphorylation.