Endophilin-A2-mediated increase in scavenger receptor expression contributes to macrophage-derived foam cell formation. (November 2016)

• Record Type: Journal Article
• Authors: Huang, Er-Wen; Liu, Can-Zhao; Liang, Si-Jia; Zhang, Zheng; Lv, Xiao-Fei; Liu, Jie; Zhou, Jia-Guo; Tang, Yong-Bo; Guan, Yong-Yuan
• Is Part Of: Atherosclerosis. Volume 254(2016)
• Page Start: 133
• Page End: 141
• Publication Date: 2016-11
• Subjects: Foam cell formation -- Scavenger receptor -- Endophilin-A2 -- ASK1; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.10.009
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Macrophage-derived foam cell formation (MFCF) is a crucial step in the pathogenesis of atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors is indispensable for MFCF. Endophilin-A2 has been reported to regulate clathrin-mediated endocytosis (CME). In this study, we tested the hypothesis that endophilin-A2 regulates oxLDL uptake and MFCF by mediating CME of oxLDL-scavenger receptor complexes. Methods: In vitro MFCF was induced by oxLDL treatment. Involvement of endophilin-A2 in oxLDL cytomembrane binding, cellular uptake, and MFCF was evaluated by manipulation of endophilin-A2. Results: Endophilin-A2 was involved in MFCF via scavenger receptor CD36 and scavenger receptor-A (SR-A)-mediated positive feedback pathways. We observed that oxLDL triggered interaction of endophilin-A2 with CD36 or SR-A, and induced an endophilin-A2-dependent activation of the apoptosis signal-regulating kinase-1 (ASK1)/Jun N-terminal kinase (JNK)/p38 signaling pathway. The activation of ASK1-JNK/p38 signal increased expression of both CD36 and SR-A, which promoted oxLDL cytomembrane binding, cellular uptake, and MFCF. In the absence of oxLDL, endophilin-A2 up-regulated the expression of receptors and Dil-oxLDL binding and uptake, but not the intracellular accumulation of lipids. In the presence of oxLDL, the CME inhibitors pitstop2 and ikarugamycin mimicked the inhibiting effect of endophilin-A2 knockdown and eliminated the elevating effect of endophilin-A2 overexpression on oxLDL uptake and MFCF. Conclusions: Endophilin-A2 was identified as a novel molecule regulating MFCF by mechanisms attributable to CME and beyond CME. Highlights: We identified endophilin-A2 as a novel macrophage-derived foam cell formation (MFCF)-regulating molecule. Endophilin-A2 regulates MFCF by regulating expression of CD36 and SR-A. Endophilin-A2 regulates MFCF by mechanisms attributable to and beyond endocytosis.