IL-33 Attenuates Anoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis by Inhibition of PKCβ/JNK Pathway

Abstract

BackgroundInterleukin-33 (IL-33) is a new member of the IL-1 cytokine family. The objectives of present study are to assess whether IL-33 can protect cardiomyocytes from anoxia/reoxygenation (A/R)-induced injury and the mechanism involved in the protection.MethodsCardiomyocytes derived from either wild type or JNK1−/− mice were challenged with an A/R with or without IL-33. Myocyte apoptosis was assessed by measuring caspase 3 activity, fragmented DNA and TUNEL staining. In addition, cardiomyocyte oxidative stress was assessed by measuring DHR123 oxidation; PKCβII and JNK phosphorylation were assessed with Western blot.ResultsChallenge of cardiomyocytes with an A/R resulted in cardiomyocyte oxidative stress, PKCβII and JNK phosphorylation, and myocyte apoptosis. Treatment of the cardiomyocytes with IL-33 attenuated the A/R-induced myocyte oxidative stress, prevented PKCβII and JNK phosphorylation and attenuated the A/R-induced myocyte apoptosis. The protective effect of the IL-33 did not show in cardiac myocytes with siRNA specific to PKCβII or myocytes deficient in JNK1. Inhibition of PKCβII prevented the A/R-induced JNK phosphorylation, but inhibition of JNK1 showed no effect on A/R-induced PKCβII phosphorylation.ConclusionsOur results indicate that IL-33 prevents the A/R-induced myocyte apoptosis through inhibition of PKCβ/JNK pathway.

Naringin protects against anoxia/reoxygenation-induced apoptosis in H9c2 cells via the Nrf2 signaling pathway

“…Previous studies have shown that Nar has a strong cardioprotective effect because of its powerful antioxidant properties. In accordance with previous studies, [31][32][33] we found that A/R induced a variety of pathological changes in H9c2 cells. 30 However, the mechanism by which Nar protects against I/R-induced myocardial injury is still not well defined.…”

Cardiomyocyte-Specific Transforming Growth Factor β Suppression Blocks Neutrophil Infiltration, Augments Multiple Cytoprotective Cascades, and Reduces Early Mortality After Myocardial Infarction

“…This demonstrates that myocyte TGFbetaR1-dependent signaling is not confined to the myocyte itself but that intercellular crosstalk originating from the myocyte can ultimately drive IL-33 expression in non-myocyte cells. Protection against ischemic injury by IL-33 has also been linked to JNK inhibition and reduced apoptosis 32, 48 , and we observed reduced JNK phosphorylation in TGFbetaR1 cKD animals.…”

“…It is a ligand for the ST2 receptor and protective against several forms of heart disease 30–32 . In infarcted control hearts, Il33 gene expression rose slightly more than 2-fold, but increased nearly 10-fold in TGFbetaR1 cKD (Figure 7A).…”

“…Intriguingly, we found many of these, including IL-33, ARMET, FSTL1 and GDF-15, were enhanced in the TGFbetaR1 cKD post-MI heart. Interleukin-33 was among the most enhanced, and while its inflammatory regulation varies with the disease 43–46 , in the heart it protects against pathological remodeling after infarction, myocyte hypoxia, and pressure-overload 30–32, 47 . Intriguingly, IL-33 was predominantly located in non-myocyte cells in the border zone.…”

Protein Kinase C Beta II (PKCβII) Peptide Inhibitor Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury

“…Reperfusion injury is initiated by decreased endothelialderived nitric oxide (NO) which occurs within 5 min of reperfusion [2], and may in part be explained by PKC II mediated activation of NADPH oxidase, which occurs upon cytokine release during MI/R [3]. PKC II activity is increased in animal models of MI/R and known to exacerbate tissue injury [4,5]. PKC II is known to increase NADPH oxidase activity in leukocytes, endothelial cells and cardiac myocytes via phox47 phosphorylation, and decrease endothelial NO synthase (eNOS) activity via phosphorylation of Thr 495 [6][7][8].…”