Cortistatin protects myocardium from endoplasmic reticulum stress induced apoptosis during sepsis.
Sepsis and septic shock are common entities encountered in intensive care units. Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis, and myocardial apoptosis is a key step for this progression, which may contribute to cardiac contractile dysfunction. Increasing evidence suggested the anti-inflammatory role of cortistatin (CST) during lethal endotoxemia. However, the direct protective effect of CST on myocardial is still not clear. Here, we aimed to study whether CST can directly protect myocardial from apoptosis. To test that, we used cecal ligation and puncture (CLP) induced sepsis rat model. CST (175 µg/kg, intraperitoneal administration) was injected every 24 h before the model induction for 3 days. Electron microscopy, TUNEL staining, caspase-3 expression, and the Bcl-2/Bax ratio were used to measure myocardial apoptosis. In addition, the protein levels of endoplasmic reticulum stress (ERS) markers were overexpressed in sepsis. To further test whether CST can directly protect myocardial apoptosis from ERS, we compared dithiothreitol (DTT) induced cardiomyocyte (CM) ERS with or without CST in vitro. We found that CST strongly attenuated lipopolysaccharide (LPS) and DTT induced CM ERS. Blocking GHS-R1a, one of CST's receptors expressed by CMs, completely abrogated CST's protective effect. Finally, CST's protective effect was associated with the decrease of ERS both in vivo and in vitro. In conclusion, our results for the first time showed the previously unexpected role of CST to directly protect myocardial from apoptosis through inhibiting ERS and partly through GHS-R1a.
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Bo
B
Zhang
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Yue
Y
Liu
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
Jin-Sheng
JS
Zhang
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Xiao-Hui
XH
Zhang
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Wen-Jia
WJ
Chen
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Electronic address: harbin0910@yahoo.com.
Xin-Hua
XH
Yin
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100191, China; Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100191, China. Electronic address: yongfenqi@yahoo.com.
Yong-Fen
YF
Qi
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D004229:Dithiothreitol / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006334:Heart Function Tests; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009479:Neuropeptides / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D054440:Receptors, Ghrelin / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology
D002316:Cardiotonic Agents; D008070:Lipopolysaccharides; D009479:Neuropeptides; D054440:Receptors, Ghrelin; C099323:cortistatin; D004229:Dithiothreitol
Apoptosis; Cortistatin; Endoplasmic reticulum stress; GHS-R1a; Sepsis