Selective Azapeptide CD36 Ligand MPE-298 Regulates oxLDL-LOX-1-Mediated Inflammation and Mitochondrial Oxidative Stress in Macrophages.

IF 5.1 2区 生物学 Q2 CELL BIOLOGY
Cells Pub Date : 2025-03-06 DOI:10.3390/cells14050385
Mukandila Mulumba, Catherine Le, Emmanuelle Schelsohn, Yoon Namkung, Stéphane A Laporte, Maria Febbraio, Marc J Servant, Sylvain Chemtob, William D Lubell, Sylvie Marleau, Huy Ong
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Abstract

Macrophage mitochondrial dysfunction, caused by oxidative stress, has been proposed as an essential event in the progression of chronic inflammation diseases, such as atherosclerosis. The cluster of differentiation-36 (CD36) and lectin-like oxLDL receptor-1 (LOX-1) scavenger receptors mediate macrophage uptake of oxidized low-density lipoprotein (oxLDL), which contributes to mitochondrial dysfunction by sustained production of mitochondrial reactive oxygen species (mtROS), as well as membrane depolarization. In the present study, the antioxidant mechanisms of action of the selective synthetic azapeptide CD36 ligand MPE-298 have been revealed. After binding to CD36, MPE-298 was rapidly internalized by and simultaneously induced CD36 endocytosis through activation of the Lyn and Syk (spleen) tyrosine kinases. Within this internalized complex, MPE-298 inhibited oxLDL/LOX-1-induced chemokine ligand 2 (CCL2) secretion, abolished the production of mtROS, and prevented mitochondrial membrane potential depolarization in macrophages. This occurred through the inhibition of the multiple-component enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by oxLDL-activated LOX-1, which was further supported by the reduced recruitment of the p47phox subunit and small GTPase (Rac) 1/2/3 into the plasma membrane. A new mechanism for alleviating oxLDL-induced oxidative stress and inflammation in macrophages is highlighted using the CD36 ligand MPE-298.

选择性氮肽CD36配体MPE-298调节巨噬细胞oxldl - lox -1介导的炎症和线粒体氧化应激。
氧化应激引起的巨噬细胞线粒体功能障碍已被认为是慢性炎症疾病(如动脉粥样硬化)进展中的重要事件。CD36簇和凝集素样oxLDL受体-1 (LOX-1)清除受体介导巨噬细胞对氧化低密度脂蛋白(oxLDL)的摄取,通过持续产生线粒体活性氧(mtROS)和膜去极化导致线粒体功能障碍。本研究揭示了选择性合成氮肽CD36配体MPE-298的抗氧化作用机制。MPE-298与CD36结合后,通过激活Lyn和Syk(脾)酪氨酸激酶,被CD36快速内化并同时诱导CD36内吞。在这个内化复合物中,MPE-298抑制oxLDL/ lox -1诱导的趋化因子配体2 (CCL2)分泌,消除mtROS的产生,并阻止巨噬细胞线粒体膜电位去极化。这是通过氧化低密度脂蛋白激活的LOX-1抑制多组分酶烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶2 (NOX2)而发生的,这进一步得到了p47phox亚基和小GTPase (Rac) 1/2/3进入质膜的募集减少的支持。CD36配体MPE-298是一种缓解巨噬细胞氧化应激和炎症的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cells
Cells Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
9.90
自引率
5.00%
发文量
3472
审稿时长
16 days
期刊介绍: Cells (ISSN 2073-4409) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided.
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