Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
J Cell Mol Med. 2020 Mar;24(6):3292-3302. doi: 10.1111/jcmm.15002. Epub 2020 Jan 22.
Atherosclerosis is regarded as a chronic progressive inflammatory disease and is a basic pathophysiological process in coronary artery disease which is life threatening in clinic. The formation of foam cell plays a key role in the pathogenesis of atherosclerosis. OxLDL is a significant factor in progression of coronary artery disease. Our studies have demonstrated that USP14 promotes cancer development and mediates progression of cardiac hypertrophy and LPS-induced inflammation. However, the underlying mechanism of USP14 is unknown. In this study, we found that the inhibition of USP14 significantly suppressed the oxLDL uptake, subsequently decreased the foam cell formation. Surprisingly, USP14 has an effect on the expression of CD36 but not SR-A, ABCA1, Lox-1, ABCG1 and SR-Bl. Furthermore, USP14 stabilizes CD36 protein via cleaving the ubiquitin chain on CD36. Blocking CD36 activation using antibody-dependent blocking assay remarkably attenuated the function of USP14 on the formation of foam cell. In summary, our results suggested that the inhibition of USP14 decreases foam cell formation by down-regulating CD36-mediated lipid uptake and provides a potential therapeutic target for atherosclerosis.
动脉粥样硬化被认为是一种慢性进行性炎症性疾病，是威胁生命的临床冠状动脉疾病的基本病理生理过程。泡沫细胞的形成在动脉粥样硬化的发病机制中起着关键作用。氧化低密度脂蛋白（OxLDL）是冠状动脉疾病进展的重要因素。我们的研究表明，USP14 促进癌症的发展，并介导心脏肥大和 LPS 诱导的炎症的进展。然而，USP14 的潜在机制尚不清楚。在这项研究中，我们发现 USP14 的抑制显著抑制了 oxLDL 的摄取，随后减少了泡沫细胞的形成。令人惊讶的是，USP14 对 CD36 的表达有影响，但对 SR-A、ABCA1、Lox-1、ABCG1 和 SR-B1 没有影响。此外，USP14 通过切割 CD36 上的泛素链来稳定 CD36 蛋白。使用抗体依赖性阻断测定法阻断 CD36 的激活，显著减弱了 USP14 对泡沫细胞形成的作用。总之，我们的结果表明，抑制 USP14 通过下调 CD36 介导的脂质摄取来减少泡沫细胞的形成，并为动脉粥样硬化提供了一个潜在的治疗靶点。
