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

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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, IMD1–53 (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. IMD1–53 also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD1–53 were abolished by the IMD receptor antagonist IMD17–47 (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 IMD1–53. Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD1–53 (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD1–53 could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant nos. 30770869, 30871013 and 81170082 to YF Qi) and the State Major Basic Research Development Program of the People’s Republic of China (grant no. 2011CB503904 to YF Qi)

Conflicts of interest

The authors have no competing financial interests to disclose in relation to this manuscript.

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Authors and Affiliations

  1. 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, Beijing, 100029, China

    Xu Teng, Yan Cai, Jie Du, Chaoshu Tang & Yongfen Qi

  2. Key Laboratory of Molecular Cardiovascular Science, Health Science Center, Peking University, Ministry of Education, Beijing, 100191, China

    Junqiu Song, Gaigai Zhang, Chaoshu Tang & Yongfen Qi

  3. Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, China

    Xu Teng & Fang Yuan

  4. Hebei Key laboratory of Laboratory Animal Science, Shijiazhuang, 050017, China

    Xu Teng & Fang Yuan

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  1. Xu Teng
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Correspondence to Yongfen Qi.

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Teng, X., Song, J., Zhang, G. et al. Inhibition of endoplasmic reticulum stress by intermedin1–53 protects against myocardial injury through a PI3 kinase–Akt signaling pathway. J Mol Med 89, 1195–1205 (2011). https://doi.org/10.1007/s00109-011-0808-5

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