Carvedilol, nonselective β-adrenoreceptor antagonist, was showed protective effects against acute myocardial infarction （AMI）-induced myocardial injury, however, the mechanisms underlying the anti- fibrosis effect of carvedilol has not been well known. The aim of the present study was to investigate the potential mechanism for the anti-fibrosis effect of carvedilol against AMI-induced myocardial fibrosis in rats. Methods Male SD rats were randomized into the sham group, LAD surgery-AMI model group, AMI plus low dose of carvedilol treatment group （1 mg/kg per day, CAR-L）, AMI plus medium dose of carvedilol treatment group （5 mg/kg per day, CAR-M） and AMI plus high dose of carvedilol treatment group （10 mg/kg per day, CAR-H）. The passage 3 neonatal SD rat cardiac fibroblasts were used for hypoxia/normoxia （2 h/4 h） treatment in the presence of carvedilol （0, 1, 2 and 4 μM）. Results Cardiac remodeling and impaired heart function were observed after 14-week LAD surgery treatment, however, and the cardiac remodeling and decreased ejection fraction （EF%） and fractional shortening （FS%） were efficiently rescued in the CAR-M and CAR-H groups. The up-regulated expressions of Collal, Col3al and tx-SMA at mRNA and protein levels were significantly reduced in the CAR-M and CAR-H groups. The in vitro study showed that Collal, Col3al and ot- SMA expressions at both mRNA and protein levels were down-regulated by carvedilol in rat cardiac fibroblasts in a dose-dependent manner. Smad3 inhibitors, SIS-3 and naringenin, could efficiently decrease Collal, Col3al and α-SMA expressions in rat cardiac fibroblasts. Smad3 was shown significantly inactivated in carvedilol-treated rat cardiac fibroblasts. Conclusion Carvedilol negatively regulates Smad3 signal pathway and inhibits extracellular matrix related Collal, Col3al and α-SMA expressions, contributing to the anti-fibrosis effect of carvedilol against AMI-induced myocardial fibrosis in rats.
Background MicroRNAs （miRNANAs） are endogenous, small non-coding RNAs that negatively regulate gene expression in diverse cardiovascular diseases. However, the roles of miRNANAs in atherosclerogenesis needs to be elucidated. In the present study, the effect of miRNA-21 on pro-atherosclerotic genes expression was examined. Methods The pro-atherosclerotic genes including COX2, VCAM1, ICAM1, MCP1 and miRNA-21 were detected in ox-LDL-treated mouse macrophage RAW264.7 cells. ApoE knock-out （ApoE- KO） mice were fed with high-fat diet for 16 weeks, and the abdominal aorta were fixed and used for miRNA- 21 hybridization. Lentivirus-based vectors for enforced expression of miRNA-21 and antisense miRNA-21were prepared. The expression of proatherosclerotic genes was determined in the RAW264.7 cells with lentivirus- mediated up-regulation of miRNA-21. Results COX2, VCAM1, ICAM1 and MCP1 could be up-regulated by ox-LDL treatment, and 50 Ixg/mL ox-LDL could significantly increase the expression of above four genes in ox-LDL EAW264.7 cells, miRNA-21 could also be markedly up-regulated in ox-LDL-induced RAW264.7 cells. The result of miRNANA hybridization showed that miRNA-21 was strongly expressed in atherosclerotic plaques but not in normal aorta. Lentivirus-mediated over-expression of miRNA-21 could significantly enhance expressions of COX2, VCAM1, ICAM1 and MCP1 in RAW264.7 cells, which could be reversed by antisense miRNA-21 mediated by lentivirus vector. Conclusions miRNA-21 could be modulated by ox-LDL in macrophage RAW264.7 cells, and miRNA-21 could enhance COX2, VCAM1, ICAM1 and MCP1 expressions in macrophages.
