Electronegative low-density lipoprotein induces cardiomyocyte apoptosis indirectly through endothelial cell-released chemokines
Abstract
Cardiomyocyte apoptosis has a critical role in the pathogenesis of heart failure. L5, the most negatively charged subfraction of human plasma low-density lipoprotein (LDL), induces several atherogenic responses in endothelial cells (ECs), including apoptosis. We hypothesized that L5 also contributes to cardiomyocyte apoptosis and studied whether it does so indirectly by inducing the secretion of factors from ECs. We examined apoptosis of rat cardiomyocytes treated with culture-conditioned medium (CCM) of rat ECs that were exposed to L5 or L1 (the least negatively charged LDL subfraction). Apoptosis at early and late time points was twofold greater in cardiomyocytes treated with L5 CCM than in those treated with L1 CCM. The indirect effect of L5 on cardiomyocyte apoptosis was significantly reduced by pretreating ECs with inhibitors of phosphatidylinositol 3-kinase (PI3K) or CXC receptor 2 (CXCR2). Studies with cytokine protein arrays revealed that L5 CCM, but not L1 CCM, contained high levels of ELR(+) CXC chemokines, including lipopolysaccharide-induced chemokine (LIX) and interleukin (IL)-8. The L5-induced release of these chemokines from ECs was abolished by inhibiting the lectin-like oxidized LDL receptor-1 (LOX-1). Addition...Continue Reading
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