The Activation Of CD36-signaling Cascade By 7-ketocholesteryl-9-carboxynonanoate

oxLDL, oxidized from low density lipoprotein is considered to be the major cause of atherosclerosis. Scavenger receptor CD36 accounts for a large portion of recognition and uptake of oxLDL, thus so many papers focused on CD36 as the targeted gene in the development of AS. The paper here focused on the effective lipid component of oxLDL, 7-ketocholesteryl-9-carboxynonanoate (oxLig-1). The similar structure between oxLig-1 and low affinity ligands for CD36 supplies references for us to explor the activation of CD36-mediated signaling cascade by 7-ketochoresteryl-9-caboxynonanoate in J774A.1.In this manuscript we demonstrated by immunoprecipitation assay that oxLig-1, a lipid moiety of oxLDL, leads to activation and recruitment of Src kinase Fyn, Lyn and caveolin-1 to CD36. No significant difference of the expression of CD36 was found by treatment of oxLig-1 for 12 hours. The mitogen-activated protein (MAP) kinases c-Jun N-terminal kinase 1 and 2 (JNK1/2) and extracelluar signal-regulated protein kinase 1 and 2 (ERK1/2) were specifically phosphorylated in macrophages exposed to oxLig-1, and inhibited by pretreatment of src kinase inhibitor, AG1879. Interestingly, oxLig-1 up-regulated the expression of ABCA1 in J774A.1 macrophages. Moreover, inhibition of JNK1/2 but not ERK1/2 by pretreatment of pharmacological inhibitors of SP600125 and PD98059, dramatically inhibited the expression of ABCA1.We also found proliferation effect induced by oxLig-1 in J774A.1 cells, and this effect was modulated through src-non receptor protein kinases, because src inhibitor AG1879 significantly inhibited the proliferation of oxLig-1. Oil red O results showed the not formation of foam cell induced by oxLig-1.Collectively, these findings suggested that a specific CD36 signal induced by oxLig-1 initiated the activation of Fyn, Lyn, Caveolin-1 and JNK1/2, finally, resulted in the up-regulating expression of ABCA1 and J774A.1 macrophages proliferation. The upregulation expression of ABCA1 but not CD36 suggesting that oxLig-1 could be a potential new candidate for anti-atherosclerosis therapy.