Inhibition of endoplasmic reticulum stress by intermedin1–53 protects against myocardial injury through a PI3 kinase–Akt signaling pathway

Abstract

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(1-53) (10(-9), 10(-8), and 10(-7) 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(1-53) also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD(1-53) were abolished by the IMD receptor antagonist IMD(17-47) (10(-6) 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(1-53). Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD(1-53) (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD(1-53) could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.

Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

“…Activation of Akt was found to rescue the cardiac mechanical function defect induced by ER stress, whereas it did not affect the protein levels of ER stress markers (14,17). Recent studies demonstrated that inhibition of ER stress by intermedin was blocked by the PI3K inhibitor (29). In the study, data depicted that Akt activity was dampened in response to a tunicamycin challenge, which was recovered by ALDH2.…”

Tanshinone IIA ameliorates apoptosis of cardiomyocytes induced by endoplasmic reticulum stress

“…4 Previous study has demonstrated that ERS contributed to myocardial injury, and some factors also improved impairment of myocardium by inhibiting ERS. 5,6 Therefore, ERS has be considered as one of main target for prevention and therapy of myocardial injury and diseases.…”

Intermedin and the unfolded protein response

“…Up-regulation of proteins involved in UPR In this issue, Teng and colleagues examined putative cardioprotective actions of intermedin [4]. The authors first prepared myocardial slices that were incubated in 24-well plates.…”

“…Teng et al [4] next investigated phosphoinositide 3-kinase and Akt signaling (PI3K/Akt). Akt is also known as protein kinase B.…”