Fan Linwei, Tang Yuanjun, Liu Jian, Liu Yueqi, Xu Yiwei, Liu Jiayu, Liu Han, Pang Wei, Guo Yuxuan, Yao Weijuan, Zhang Tao, Peng Qin, Zhou Jing
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, 100191, China.
Shenzhen Bay Laboratory, Shenzhen, 518132, China.
Adv Sci (Weinh). 2025 Jan;12(3):e2411559. doi: 10.1002/advs.202411559. Epub 2024 Nov 26.
High-magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)/ Yin Yang 1 (YY1)/ carnitine palmitoyltransferase 1b (CPT1B) signaling in coordinating VSMC mechanical activation by inhibiting fatty acid β-oxidation. Metabolomic analysis showed that a 15%-1 Hz arterial cyclic stretch, compared to a 5%-1 Hz venous stretch, increased long-chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%-1 Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid β-oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. Overexpressing CPT1B or inhibiting cPLA2 reduced VSMC proliferation and migration in vein grafts, decreasing neointimal hyperplasia. This study uncovers a novel mechanism in lipid metabolic reprogramming in vein grafts, suggesting a new therapeutic target for vein graft hyperplasia.
动脉血压产生的高强度周期性拉伸显著促进了血管平滑肌细胞（VSMC）的过度增殖和迁移，导致静脉移植物中新生内膜的形成。然而，其分子机制仍不清楚。本研究强调了胞质磷脂酶A2（cPLA2）/阴阳1（YY1）/肉碱棕榈酰转移酶1b（CPT1B）信号在通过抑制脂肪酸β-氧化来协调VSMC机械激活中的关键作用。代谢组学分析表明，与5%-1Hz的静脉拉伸相比，15%-1Hz的动脉周期性拉伸增加了VSMC中的长链脂肪酸。cPLA2被鉴定为一种机械反应性分子，在15%-1Hz的拉伸下会产生过量的花生四烯酸（ArAc），抑制脂肪酸β-氧化中的关键酶CPT1B的表达。ArAc促进转录因子YY1的降解，下调CPT1B。CPT1B或YY1的敲低或依托莫昔芬处理导致的脂肪酸氧化不足，增加了核膜张力，从而协调了cPLA2的激活。过表达CPT1B或抑制cPLA2可减少静脉移植物中VSMC的增殖和迁移，减少新生内膜增生。本研究揭示了静脉移植物中脂质代谢重编程的一种新机制，为静脉移植物增生提供了一个新的治疗靶点。
