CaMKIIδ Mediates Myocardial Ischemia/Reperfusion Injury Through NF-κB

Details

• Alternative Title:
  Circ Res
• Personal Author:
  Ling, Haiyun ; Gray, Charles B.B. ; Zambon, Alexander C. ; Grimm, Michael ; Gu, Yusu ; Dalton, Nancy ; Purcell, Nicole H. ; Peterson, Kirk ; Brown, Joan Heller
• Description:
  Rationale
  
  Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been implicated as a maladaptive mediator of cardiac ischemic injury. We hypothesized that the inflammatory response associated with in vivo ischemia/reperfusion (I/R) is initiated through CaMKII signaling.
  
  Objective
  
  To assess the contribution of CaMKIIδ to the development of inflammation, infarct and ventricular dysfunction following in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKIIδ using cardiac-specific knockout (KO) mice.
  
  Methods and Results
  
  Wild-type (WT) and CaMKIIδ KO mice were subjected to in vivo I/R by occlusion of the left anterior descending (LAD) artery for 1-hr followed by reperfusion for various times. CaMKIIδ deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis and improved functional recovery. CaMKIIδ deletion also attenuated I/R induced inflammation and upregulation of NF-κB target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-κB activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKIIδ knockout mice indicate that NF-κB activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes lead to I kappa B kinase (IKK) phosphorylation and concomitant increases in nuclear p65. Experiments using an IKK inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-κB activation.
  
  Conclusions
  
  This is the first study demonstrating that CaMKIIδ mediates NF-κB activation in cardiomyocytes following in vivo I/R and suggests that CaMKIIδ serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage.
  
  
• Subjects:
  Animals Apoptosis Article Ca2+/calmodulin-dependent Protein Kinase II Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cyclosporine Gene Expression Profiling Heart I-kappa B Proteins Ischemic Heart Disease Mice Mice, Knockout Myocardial Infarction Myocardial Inflammation Myocardial Reperfusion Injury Myocardium Myocytes, Cardiac NF-kappa B Nuclear Factor Kappa B Phosphorylation Recovery Of Function Reperfusion Injury Transcription Factor RelA Up-Regulation

  More +
• Source:
  Circ Res. 112(6):935-944.
• Pubmed ID:
  23388157
• Pubmed Central ID:
  PMC3673710
• Document Type:
  Journal Article
• Funding:
  P01HL098053/HL/NHLBI NIH HHS/United States ; P01 HL080101/HL/NHLBI NIH HHS/United States ; 8UL1TR000100-03/TR/NCATS NIH HHS/United States ; 1U54HK08460-01/HK/PHITPO CDC HHS/United States ; T32 GM007752/GM/NIGMS NIH HHS/United States ; UL1 TR000100/TR/NCATS NIH HHS/United States ; HL080101/HL/NHLBI NIH HHS/United States ; P01 HL098053/HL/NHLBI NIH HHS/United States
• Volume:
  112
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0f518223b0a70cfba5c080cc7cc462e52e1c228f92e19884e96ea03fba9a9936
• Download URL:
  https://stacks.cdc.gov/view/cdc/29670/cdc_29670_DS1.pdf
• File Type:
  [PDF - 2.26 MB ]