title: Reduction in IL-33 expression exaggerates ischaemia/reperfusion-induced myocardial injury in mice with diabetes mellitus.
abstract: OBJECTIVE
  The underlying mechanism(s) of vulnerability of the diabetic myocardium to ischaemia/reperfusion (I/R)-induced injury is not fully understood. Interleukin-33 (IL-33) has been reported showing the beneficial effect to the myocardium on I/R injury. The aims of this study were to test whether diabetes mellitus (DM) affects myocardial levels of IL-33 and to examine whether reduction in IL-33 is responsible for exaggerated I/R injury in the diabetic myocardium.
  
  
  RESULTS
  DM hearts were challenged with I/R in vivo, whereas while isolated cardiomyocytes in vitro were conditioned with high glucose (HG) followed by an anoxia/reoxygenation (A/R) challenge. Myocardial levels of IL-33 were decreased in mice with DM which was associated with increased protein kinase C βII (PKCβII) activation. Exogenous IL-33 prevented the DM-induced PKCβII activation and attenuated I/R injuries (myocardial infarction size and apoptosis). HG-conditioned myocytes incurred exaggerated apoptosis when compared with naïve myocytes after A/R which was attenuated by IL-33. HG activated PKCβII in cardiomyocytes, which was further enhanced by A/R. IL-33 prevented the PKCβII activation in myocytes with HG or HG and A/R. Inhibition of PKCβII prevented the beneficial effect of IL-33. Finally, IL-33 up-regulated diacylglycerol kinase zeta (DGK-zeta) in cardiomyocytes and reversed the down-regulation of myocardial DGK-zeta in mice with DM.
  
  
  CONCLUSIONS
  Our results indicate that decreased levels of IL-33 are responsible for the increased sensitivity of the myocardium to I/R in DM. Reduction in IL-33 results in a chronic activation of PKCβII. I/R further enhances PKCβII activation in the diabetic myocardium which results in exaggeration of myocardial injury.
authors.affiliation: Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China. trui@uwo.ca
authors.forename: Tao
authors.initials: T
authors.lastname: Rui
authors.forename: Jinchao
authors.initials: J
authors.lastname: Zhang
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xu
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Yao
authors.forename: Raymond
authors.initials: R
authors.lastname: Kao
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis; D048909:Diabetes Complications / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta
chemical_list: C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D011493:Protein Kinase C; D064546:Protein Kinase C beta