Beraprost sodium attenuates the development of myocardial fibrosis after myocardial infarction by regulating GSK-3ß expression in rats.

OBJECTIVE: The aim of this study was to elucidate the mechanism of beraprost sodium (BPS) in the intervention of myocardial fibrosis after myocardial infarction (MI) through glycogen synthase kinase-3ß (GSK-3ß) and to provide new ideas for intervention in myocardial fibrosis. MATERIALS AND METHODS: MI model rats given BPS and cardiac fibroblasts (CFs) treated with BPS and TGF-ß. HE staining and Masson staining were used to detect the pathological changes of myocardial tissue. Fibrotic markers were detected by immunohistochemical staining. The expressions of GSK-3ß, cAMP response element binding protein (CREB), and p-CREB were analyzed by qPCR and western blot analysis. EDU staining was used to detect the proliferation of CFs. The promoter activity of GSK-3ß was detected by luciferase assay. Chromatin immunoprecipitation assay was used to detect the binding levels of GSK-3ß promoter and Y-box binding protein 1 (YBX1). The levels of intracellular cyclic adenosine monophosphate (cAMP) were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: After operation, BPS improved myocardial fibrosis and upregulated GSK-3ß protein expression in male SD rats. BPS can down-regulate α-smooth muscle actin (α-SMA) level and up-regulate GSK-3ß protein expression in CFs after TGF-ß stimulation. Furthermore, GSK-3ß knockdown can reverse the effect of BPS on TGF-ß-activated CFs, enhance α-SMA expression, and promote the proliferation of CFs. BPS could regulate GSK-3ß expression by promoting the binding of GSK-3ß promoter to YBX1. BPS induced upregulation of p-CREB and cAMP, resulting in reduced fibrosis, which was reversed by the knockdown of GSK-3ß or prostaglandin receptor (IPR) antagonists. CONCLUSION: BPS treatment increased the binding of YBX1 to the GSK-3ß promoter, and GSK-3ß protein expression was upregulated, which further caused the upregulation of p-CREB and cAMP, and finally inhibited myocardial fibrosis.

Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression. METHODS AND RESULTS: Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P=0.007), MMP-22 (OR=1.213, P=0.040), and MMP-29 (OR=1.198, P=0.033) were independent risk factors of CHD. Pearson's correlation test showed that IL18 (coefficient (r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22 (r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson's correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) (r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride (r=-0.169, P=0.018). Spearman's correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 (r=0.845, P<0.001) and MMP-29 (r=0.548, P<0.001). CONCLUSIONS: Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29 levels in these patients.