CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

Gray, Charles B.B.; Suetomi, Takeshi; Xiang, Sunny; Mishra, Shikha; Blackwood, Erik A; Glembotski, Christopher C.; Miyamoto, Shigeki; Westenbrink, B. Daan; Brown, Joan Heller

doi:10.1016/j.yjmcc.2017.01.002

Cited by 66 publications

(65 citation statements)

References 38 publications

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“…There is increasing evidence for a link between CaMKII and NF-B signalling, however our understanding of this link in the heart remains limited [15,16,24]. This is the first study to present evidence for a direct interaction between a specific component of the pathway (IKK) and CaMKIIand to demonstrate a functional interaction in CFs.…”

Section: Discussionmentioning

confidence: 90%

CaMKIIδ interacts directly with IKKβ and modulates NF-κB signalling in adult cardiac fibroblasts

Martin

McCluskey

Cunningham

et al. 2018

Cellular Signalling

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Calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) acts as a molecular switch regulating cardiovascular Ca handling and contractility in health and disease. Activation of CaMKIIδ is also known to regulate cardiovascular inflammation and is reported to be required for pro-inflammatory NF-κB signalling. In this study the aim was to characterise how CaMKIIδ interacts with and modulates NF-κB signalling and whether this interaction exists in non-contractile cells of the heart. Recombinant or purified CaMKIIδ and the individual inhibitory -κB kinase (IKK) proteins of the NF-κB signalling pathway were used in autoradiography and Surface Plasmon Resonance (SPR) to explore potential interactions between both components. Primary adult rat cardiac fibroblasts were then used to study the effects of selective CaMKII inhibition on pharmacologically-induced NF-κB activation as well as interaction between CaMKII and specific IKK isoforms in a cardiac cellular setting. Autoradiography analysis suggested that CaMKIIδ phosphorylated IKKβ but not IKKα. SPR analysis further supported a direct interaction between CaMKIIδ and IKKβ but not between CaMKIIδ and IKKα or IKKγ. CaMKIIδ regulation of IκΒα degradation was explored in adult cardiac fibroblasts exposed to pharmacological stimulation. Cells were stimulated with agonist in the presence or absence of a CaMKII inhibitor, autocamtide inhibitory peptide (AIP). Selective inhibition of CaMKII resulted in reduced NF-κB activation, as measured by agonist-stimulated IκBα degradation. Importantly, and in agreement with the recombinant protein work, an interaction between CaMKII and IKKβ was evident following Proximity Ligation Assays in adult cardiac fibroblasts. This study provides new evidence supporting direct interaction between CaMKIIδ and IKKβ in pro-inflammatory signalling in cardiac fibroblasts and could represent a feature that may be exploited for therapeutic benefit.

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Section: Discussionmentioning

confidence: 90%

CaMKIIδ interacts directly with IKKβ and modulates NF-κB signalling in adult cardiac fibroblasts

Martin

McCluskey

Cunningham

et al. 2018

Cellular Signalling

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“…Furthermore, after I/R, cardiac function was significantly better preserved in PUMA(-/-) mice than in their wild-type littermates [14]. Cardiac I/R could activate NF-κB, and pharmacological inhibition of NF-κB significantly ameliorated infarct formation in WT mice, implicating acute activation of NF-κB in the pathogenesis of reperfusion injury [15]. Wang et al has reported that PUMA is directly activated by NF-κB in response to TNF-α treatment in a p53independent manner [16].…”

Section: Introductionmentioning

confidence: 96%

Targeting MIAT reduces apoptosis of cardiomyocytes after ischemia/reperfusion injury

Chen¹,

Zhang²,

Yu³

et al. 2019

Bioengineered

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This study aims to investigate the role of targeting lncRNA myocardial infarction-associated transcript (MIAT) in protection against hypoxia/reoxygenation (H/R) injury in H9c2 cells in vitro and myocardial ischemia/reperfusion (I/R) injury in vivo by regulating expression of NF-kB and p53 upregulated modulator of apoptosis (PUMA). H9C2 cells were infected with lentivirus expressing the short-hairpin RNA direct against human MIAT gene (Lv-MIAT shRNA) or lentivirus expressing scrambled control (Lv-NC shRNA) or PUMA siRNA or p65 siRNA or their control siRNA respectively. Then the H9c2 cells were infected with Lv-shRNA to 2 hours of hypoxia (H) and 24 hour of reoxygenation (R). 100 ul of Lv-MIAT shRNA (1 × 10 8 PFU) or Lv-NC shRNA was transfected into mouse hearts, then the hearts were subjected to I/R (1h/72 h). We discovered targeting MIAT remarkably enhanced H9c2 cell viability, decreased H/R-induced cell apoptosis and LDH leakage and significantly decreased I/R-induced myocardial infarct size, reduced myocardial apoptosis and enhanced the heart function. Targeting MIAT downregulated p65 nuclear translocation, NF-κB activity and anti-apoptotic protein cleaved-caspase-3, Bax, and upregulated anti-apoptotic protein Bcl-2 induced by H/R or I/R. Our study suggests that targeting MIAT may protect against H9c2 cardiomyoblasts H/R injury or myocardial I/R injury via inhibition of cell apoptosis, mediated by NF-κB and PUMA signal pathway. ARTICLE HISTORY

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“…Previous work from our laboratory and those of others demonstrated that calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ) and the transcription factor NF-κB play a regulatory role in development of inflammation induced by ischemic injury (24)(25)(26). Cardiomyocyte CaMKIIδ is also activated in response to Inflammation accompanies heart failure and is a mediator of cardiac fibrosis.…”

Section: Introductionmentioning

confidence: 96%

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

Willeford¹,

Suetomi²,

Nickle³

et al. 2018

JCI Insight

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106

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Inflammation accompanies heart failure and is a mediator of cardiac fibrosis. CaMKIIδ plays an essential role in adverse remodeling and decompensation to heart failure. We postulated that inflammation is the mechanism by which CaMKIIδ contributes to adverse remodeling in response to nonischemic interventions. We demonstrate that deletion of CaMKIIδ in the cardiomyocyte (CKO) significantly attenuates activation of NF-κB, expression of inflammatory chemokines and cytokines, and macrophage accumulation induced by angiotensin II (Ang II) infusion. The inflammasome was activated by Ang II, and this response was also diminished in CKO mice. These events occurred prior to any evidence of Ang II-induced cell death. In addition, CaMKII-dependent inflammatory gene expression and inflammasome priming were observed as early as the third hour of infusion, a time point at which macrophage recruitment was not evident. Inhibition of either the inflammasome or monocyte chemoattractant protein 1 (MCP1) signaling attenuated macrophage accumulation, and these interventions, like cardiomyocyte CaMKIIδ deletion, diminished the fibrotic response to Ang II. Thus, activation of CaMKIIδ in the cardiomyocyte represents what we believe to be a novel mechanism for initiating inflammasome activation and an inflammatory gene program that leads to macrophage recruitment and ultimately to development of fibrosis.

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CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

Cited by 66 publications

References 38 publications

CaMKIIδ interacts directly with IKKβ and modulates NF-κB signalling in adult cardiac fibroblasts

CaMKIIδ interacts directly with IKKβ and modulates NF-κB signalling in adult cardiac fibroblasts

Targeting MIAT reduces apoptosis of cardiomyocytes after ischemia/reperfusion injury

CaMKIIδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis

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