Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Dec;1869(8):166805. doi: 10.1016/j.bbadis.2023.166805. Epub 2023 Jul 17.
Neoatherosclerosis (NA), the main pathological basis of late stent failure, is the main limitation of interventional therapy. However, the specific pathogenesis and treatment remain unclear. In vivo, NA model was established by carotid wire injury and high-fat feeding in ApoE mice. Oxidized low-density lipoprotein receptor-1/lectin-like oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), a specific receptor for oxidized low-density lipoprotein (ox-LDL), was specifically ectopically overexpressed in hepatocytes by portal vein injection of adeno-associated serotype 8 (AAV8)-thyroid binding globulin (TBG)-Olr1 and the protective effect against NA was examined. In vitro, LOX-1 was overexpressed on HHL5 using lentivirus (LV)-OLR1 and the vascular smooth muscle cells (VSMCs)-HHL5 indirect co-culture system was established to examine its protective effect on VSMCs and the molecular mechanism. Functionally, we found that specific ectopic overexpression of LOX-1 by hepatocytes competitively engulfed and metabolized ox-LDL, alleviating its resulting phenotypic transformation of VSMCs including migration, downregulation of contractile shape markers (smooth muscle α-actin (SMαA) and smooth muscle-22α (SM22α)), and upregulation of proliferative/migratory shape markers (osteopontin (OPN) and Vimentin) as well as foaminess and apoptosis, thereby alleviating NA, which independent of low-density lipoprotein (LDL) lowering treatment (evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9)). Mechanistically, we found that overexpression of LOX-1 in hepatocytes competitively engulfed and metabolized ox-LDL through upregulation of arachidonate-15-lipoxygenase (ALOX15), which further upregulated scavenger receptor class B type I (SRBI) and ATP-binding cassette transporter A1 (ABCA1). In conclusion, the overexpression of LOX-1 in liver protects VSMCs from phenotypic transformation and wire injury induced carotid neoatherosclerosis through ALOX15.
新生动脉粥样硬化（NA）是支架晚期失败的主要病理基础，也是介入治疗的主要局限性。然而，其具体发病机制和治疗方法仍不清楚。在体内，通过颈动脉线损伤和高脂喂养apoE 小鼠建立了 NA 模型。通过门静脉注射腺相关病毒血清型 8（AAV8）-甲状腺结合球蛋白（TBG）-Olr1，在肝细胞中特异性异位过表达氧化型低密度脂蛋白受体-1/凝集素样氧化型低密度脂蛋白受体-1（OLR1/LOX-1），检测其对 NA 的保护作用。在体外，使用慢病毒（LV）-OLR1 在 HHL5 上过表达 LOX-1，并建立 LOX-1 血管平滑肌细胞（VSMCs）-HHL5 间接共培养系统，以检测其对 VSMCs 的保护作用及其分子机制。功能上，我们发现肝细胞特异性异位过表达 LOX-1 通过竞争性吞噬和代谢 ox-LDL，减轻其导致的 VSMCs 表型转化，包括迁移、下调收缩性形态标志物（平滑肌α-肌动蛋白（SMαA）和平滑肌 22α（SM22α））和上调增殖/迁移性形态标志物（骨桥蛋白（OPN）和波形蛋白）以及泡沫化和细胞凋亡，从而减轻新生动脉粥样硬化，这种作用独立于低密度脂蛋白（LDL）降低治疗（evolocumab，一种针对前蛋白转化酶枯草溶菌素/kexin 9 型（PCSK9）的单克隆抗体）。机制上，我们发现肝细胞中 LOX-1 的过表达通过上调花生四烯酸 15-脂氧合酶（ALOX15）竞争性吞噬和代谢 ox-LDL，进一步上调清道夫受体 B 类 I 型（SRBI）和三磷酸腺苷结合盒转运蛋白 A1（ABCA1）。总之，肝脏中 LOX-1 的过表达通过 ALOX15 保护 VSMCs 免受表型转化和线损伤诱导的颈动脉新生动脉粥样硬化。
