title: Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.
abstract: OBJECTIVE
  Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process.
  
  
  METHODS
  Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses.
  
  
  RESULTS
  Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 μmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA.
  
  
  CONCLUSIONS
  BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Guo-long
authors.initials: GL
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Yu
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Wen-li
authors.initials: WL
authors.lastname: Gao
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wei-xun
authors.initials: WX
authors.lastname: Duan
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Xu-dong
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen-hua
authors.initials: ZH
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Meng-en
authors.initials: ME
authors.lastname: Zhai
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen-xiao
authors.initials: ZX
authors.lastname: Jin
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shi-qiang
authors.initials: SQ
authors.lastname: Yu
authors.affiliation: Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D001599:Berberine; C507927:Jak2 protein, rat; D053614:Janus Kinase 2