title: Inhibition of endoplasmic reticulum stress by intermedin(1-53) 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.
authors: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, China.
authors: Xu
authors: X
authors: Teng
authors: Junqiu
authors: J
authors: Song
authors: Gaigai
authors: G
authors: Zhang
authors: Yan
authors: Y
authors: Cai
authors: Fang
authors: F
authors: Yuan
authors: Jie
authors: J
authors: Du
authors: Chaoshu
authors: C
authors: Tang
authors: Yongfen
authors: Y
authors: Qi
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053454:Caspase 12 / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000188:drug therapy; D009206:Myocardium / Q000378:metabolism*; D036361:Peptide Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002316:Cardiotonic Agents; D053454:Caspase 12; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007770:L-Lactate Dehydrogenase; D008315:Malondialdehyde; D008565:Membrane Proteins; D036361:Peptide Hormones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051742:Transcription Factor CHOP; C484330:ADM2 protein, human; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C018551:glucose-regulated proteins