Abstract 20707: Role of Il-10 in the Modulation of Oxidized Phospholipids During Ischemia/Reperfusion (i/r) Injury in the Heart

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Abstract

Oxidized phosphatidylcholines (OxPCs) have been shown to play a crucial role in pathophysiological response during inflammation. These OxPCs are also generated by cardiomyocytes during myocardial I/R and promote inflammation by activating some of the receptors such as toll-like receptors (TLRs). Recent studies have shown that anti-inflammatory cytokine IL-10 inhibits 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC)-induced cell-cell interaction as well as atherosclerotic lesion formation in mice. However, the mechanism of action by which IL-10 modulates OxPCs in myocardial I/R injury needs to be elucidated. We explored the mechanistic role of IL-10 in altering OxPCs production during global I (20min) /R (90min) injury in rats. We found that I/R injury promoted the production of OxPCs and inclusion of IL-10 (10ng/ml)in the R phase improved cardiac function and abrogated the non-fragmented OxPCs production. IL-10 was extremely effective in reducing OxLDL-induced cellular damage as was evident from increased cell viability and it also improved myeloid differentiation gene factor 88 (MyD88)-dependent TLR4 activity. The phosphorylation of sterol regulatory element binding proteins (SREBPs) was increased in IL-10-induced cardiomyocytes along with an activation of TLR4 suggesting that there is a strong interaction with IL-10-induced activation of TLR4. IL-10 administration prevented the loss of SREBP-1cser372 during I/R injury and improved the levels of non-oxidized phospholipid such as phosphatidylecholines (PC) and sphingomyelin (SM) instead of OxPCs. Overall, an activation of IL-10/TLR4 innate signaling modulated the OxPCs production via the activation of SREBP-1receptors. Thus IL-10 cytokine may help in restoring the heart health from ischemia/reperfusion injury. (Supported by Tri-Council Research Manitoba funding.)

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