Search

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We aimed to explore whether the cardioprotective effect of IMD is mediated by inhibiting myocardial endoplasmic reticulum (sarcoplasmic reticulum) stress (ERS). In vitro, IMD (10, 10, and 10 mol/l) directly inhibited the upregulation of ERS markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and caspase-12 induced by the ERS inducers tunicamycin (Tm, 10 mg/ml) or dithiothreitol (DTT, 2 mmol/l) in cardiac tissue. IMD also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD were abolished by the IMD receptor antagonist IMD (10 mol/l) and phosphoinositide 3-kinase inhibitor LY294002 (10 μmol/l). However, preincubation with PD98059 (20 μmol/l), an extracellular signal-regulated protein kinase inhibitor, and H89 (10 μmol/l), a protein kinase A inhibitor, could not block the ERS-inhibiting effects of IMD. Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Clinical studies have suggested that metformin, a widely used antidiabetic agent, exerts a direct cardioprotective effect on cardiovascular disease in addition to its blood glucose-lowering activity. This study was designed to identify the role of metformin in rats with isoproterenol (ISO)-induced myocardial injury and to investigate its underlying mechanism. A rat model of myocardial ischemic injury was established by the subcutaneous injection of a high dose of ISO, a beta-adrenergic agonist. The results showed that pretreatment of metformin significantly reduced rat mortality induced by ISO, attenuated the increased plasma lactate dehydrogenase activity and myocardium malondialdehyde level, alleviated the hemodynamic disturbance, inhibited the upregulated gene expression of myocardial probrain natriuretic peptide and alleviated the myocardial morphological injury and apoptosis induced by ISO. Furthermore, western blot analysis showed that metformin suppressed the overexpression of the endoplasmic reticulum stress (ERS) markers cleaved caspase-12 and CEBP-homologous protein induced by ISO and increased the phosphorylation of AMP-activated protein kinase (AMPK). In conclusion, these data suggest that metformin might protect the myocardium against acute ischemic injury in rats at least partially by activating AMPK and alleviating aberrant ERS. These findings might provide further experimental evidence for treating patients at risk of ischemic heart disease with metformin.