TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation

医学 赖氨酸 HDAC3型 衰老 组蛋白 细胞生物学 血管平滑肌 平滑肌 组蛋白H3 癌症研究 内科学 生物化学 组蛋白脱乙酰基酶 氨基酸 生物 基因
作者
Xuesong Li,Minghong Chen,Xiang Chen,Xian He,Xinyu Li,Huiyuan Wei,Yongkang Tan,Min Jiao,Tayyiba Azam,Mengdie Xue,Yunjia Zhang,Mengdie Dong,Quanwen Yin,Longbin Zheng,Hong Jiang,Da Huo,Xin Wang,Shaoliang Chen,Yong Ji,Hongshan Chen
出处
期刊:European Heart Journal [Oxford University Press]
被引量:6
标识
DOI:10.1093/eurheartj/ehae379
摘要

Abstract Background and Aims Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. Methods TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT–qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. Results VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. Conclusions This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.
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