title: Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2.
abstract: OBJECTIVE
  IL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM.
  
  
  METHODS
  In the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants.
  
  
  RESULTS
  Myocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration.
  
  
  CONCLUSIONS
  Elevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. liuzhongweicn@gmail.com.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. dr.zhaona@qq.com.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. 294216621@qq.com.
authors.forename: Huolan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. axemaxme@sina.com.
authors.forename: Shunming
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. parker1985@sina.com.
authors.forename: Shuo
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. xujingsapph@yeah.net.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. 13519141540@139.com.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. zhangyong971292@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, No.257, Western Friendship Rd, Xi'an, People's Republic of China. junkuiwang@yeah.net.
authors.forename: Junkui
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006360:Heat-Shock Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053592:Interleukin-1 Receptor-Associated Kinases; D053583:Interleukin-1beta; D051742:Transcription Factor CHOP; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000594089:IL1B protein, rat