The role of ERK1/2 signaling pathway in coronary microembolization-induced rat myocardial inflammation and injury

Objectives In this work,we explore the effect of atorvastatin on myocardial apoptosis and caspase-8 acti- vation after coronary microembolization(CME) in rats. Methods Fifty rats were randomly divided into five groups; the coronary microembolization(CME) group,the sham-operated (sham) control group,the gastric lavage control group, the atorvastatin lavage group,and the caspasse-8 inhibitor (N-acetyl-Ile-Glu-Thr-Asp-CHO,abbreviated as CHO) group,with 10 rats for each group.A microembolization ball was injected through the left ventricle for constructing the CME model.Animals in the sham control group were given an injection of physiological saline instead of the microembolization ball.Seven days before the operation,the atorvastatin group underwent gastric lavage with 20 mg/kg of atorvastatin once a day.Gastric lavage control animals underwent gastric lavage with an equivalent dose of physiological saline instead of the atorvastatin.Animals in the CHO group were given an intraperitoneal injection of 10 mg/kg of CHO 30 min before the operation.Six hours after the operation,cardiac ultrasonic detection was conducted on each group to measure the cardiac function indexes.TUNEL(Terminal-deoxynucleoitidyl transferase mediated dUTP nick end labeling) assays were used to measure myocardial apoptosis,and western blots were used to quantify the expression levels of activated caspase-3 and -8.Results(1) The echocardiographic parameters showed that,compared to the sham control animals,the left ventricular ejection fraction(LVEF) of the CME group was significantly decreased(P【0.05).In addition, cardiac sonography revealed a decrease in the left ventricular shortening fraction(FS) and cardiac output(CO), but an increase in the left ventricular end-diastolic dimension (LVEDd).Compared to the CME group,the atorvastatin and CHO groups exhibited significantly improved cardiac function (P【0.05).(2) When compared with the sham control,the myocardical apoptotic rate of the CME group,as well as the levels of activated caspase-3 and-8,increased significantly (P【0.05).The myocardial apoptotic rate,as well as the levels of activated caspase-3 and caspase-8 in the atorvastatin and CHO groups,decreased significandy(P【0.05) in comparison to the CME group.Conclusions The atorvastatin pretreatment clearly suppressed post-CME myocardial apoptosis and improved cardiac function.The most likely mechanism for these effects is the blockade of the myocardial death receptor -mediated apoptosis pathway.

Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition

Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3 T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia.