High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling
High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling
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DOI：
10.1007/s11010-016-2895-7
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发表时间：
2017-03-01
影响因子：
4.3
通讯作者：
Jayakumari, N.
中科院分区：
文献类型：
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作者：
Sini, S.;Deepa, D.;Jayakumari, N.
虽然高密度脂蛋白具有动脉粥样硬化保护作用，但在慢性炎症条件下，它可能变得功能失调并增加心血管风险。我们以前证明，从记录的冠状动脉疾病的受试者的HDL是功能障碍，是促氧化/促炎症巨噬细胞。在这里，我们研究了功能障碍/促炎HDL（piHDL）对人巨噬细胞中脂质蓄积的影响，与功能HDL（nHDL）相比。与nHDL相反，巨噬细胞暴露于piHDL导致氧化应激和从piHDL显著摄取脂质，导致泡沫细胞表型的形成，如油红O染色所示，伴随总细胞胆固醇含量的增加。免疫印迹结果表明，piHDL显著上调巨噬细胞清道夫受体CD 36的表达，抑制ABCG 1和SRB 1的表达，从而促进巨噬细胞胆固醇内流能力。然后，我们确定了CD 36并不单独起作用，实际上，它在巨噬细胞中与ERK/MAPK一起沿着被激活，响应于piHDL，这反过来导致脂质积累以及通过NF κ B的激活和随后的促炎标记物-TNF-1和MMP-9的释放的促炎反应。这些作用使用CD 36或ERK/MAPK的药理学抑制剂证实。此外，piHDL处理适度激活了PPAR-gamma和Nrf 2（巨噬细胞中CD 36的已知调节剂），表明两种形式的HDL差异性地调节CD 36表达。总之，结果表明，一种新的CD 36-ERK/MAPK依赖性机制参与了piHDL引起的巨噬细胞脂质蓄积，从而揭示了HDL功能缺陷的重要性及其与动脉粥样硬化形成的潜在联系。
Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-Inotsign and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-gamma and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK-dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis.