Abstract
Oxidized phospholipids (OxPLs) promote inflammation as well as low density lipoprotein (LDL) uptake in a variety of physiological and pathological states. Given the anti-inflammatory role of the cytokine IL-10, we investigated its modulatory effect on the production of oxidized phosphatidylcholines (OxPCs) as well as lipid metabolic responses in global myocardial ischemia/reperfusion (I/R) injury. Increased OxPCs levels, by 1-Palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (POVPC), promoted oxidative stress (OS) and cell death. OxPCs-mediated-OS, resulted in oxidized low-density lipoprotein receptor 1 (LOX-1) activation and upregulated the expression of toll-like receptor 2 (TLR2). IL-10-induced increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulated LOX-1 as well as TLR2 inflammatory responses. Under stress conditions, phosphorylation of sterol regulatory element binding protein 1c (SREBP 1c) was prevented by IL-10. The latter also prevented the generation of OxPCs and reduced their ratio (OxPCs/PCs) during injury. LOX-1 activation also promoted SREBP1c-mediated TGF-βRII expression which was inhibited by IL-10. Both fragmented and non-fragmented OxPCs were elevated during I/R and this effect was attenuated by IL-10. The largest impact (two–threefold change at log2) was on PAzPC, (1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine)—a fragmented OxPC. Thus it appears that among different OxPCs, IL-10 significantly reduces a single molecule (PAzPC)-mediated lipid metabolic responses in cardiomyocytes thereby mitigating inflammation and cell death.
Highlights
Oxidized phospholipids (OxPLs) promote inflammation as well as low density lipoprotein (LDL) uptake in a variety of physiological and pathological states
We have previously reported that during global I/R injury, the recovery of the left ventricle performance was improved by the addition of IL-10 during reperfusion[38]
We show that IL-10 induced protection during I/R may be through an attenuation of fragmented oxidized phosphatidylcholines (OxPCs) activity
Summary
Oxidized phospholipids (OxPLs) promote inflammation as well as low density lipoprotein (LDL) uptake in a variety of physiological and pathological states. Increased OxPCs levels, by 1-Palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (POVPC), promoted oxidative stress (OS) and cell death. One of the derivatives of the fragmented oxidized phospholipids, 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (POVPC), is a known potent protein modifier due to a presence of the aldehyde group[6] These OxPCs may bind covalently with free amino groups of different receptors and activate signaling pathways[7,8]. The role of these OxPCs in stress-induced cell signaling has been shown through the phosphorylation of p38 mitogenactivated protein kinase (p38MAPK) which is known to promote a poptosis[9,10,11,12]. We have shown that inhibition of OxPCs activity by anti-OxPC antibody E06 caused a significant reduction in M I4
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