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Histone Lactylation–Mediated Metabolic Remodeling in Vascular Smooth Muscle Cells Aggravates Aortic Aneurysm and Dissection by Promoting Lactate Accumulation

医学 组蛋白 主动脉瘤 主动脉 血管平滑肌 血管疾病 解剖(医学) 内分泌学 新陈代谢 内科学 平滑肌 主动脉夹层 癌症研究 组蛋白H4 糖酵解 血管 心脏病学 内皮 细胞生物学 动脉瘤 细胞代谢 病理生理学 信号转导 组蛋白H3 细胞 胚胎血管重塑 表型 肌动蛋白 病理 血管组织
作者
Liwei Liu,Jinyan Zhang,Z H Dong,Yikai Cui,Xiaoyi Zou,Hao Lai,Jiawei Gu,Xinyu Weng,Xuejuan Jin,Tianyi Qiu,Zhiqiang Pei,Wenxuan Hong,Ya Huang,Wei Luo,Lihong Pan,Xiaolei Sun,Beijian Zhang,Adilan Shalamu,Aijun Sun,Junbo Ge
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:153 (3): 189-209 被引量:9
标识
DOI:10.1161/circulationaha.125.072576
摘要

BACKGROUND: Vascular smooth muscle cells (VSMCs) undergo phenotypic changes during the development of aortic aneurysm and dissection (AAD). Metabolism shifts from oxidative phosphorylation to glycolysis. Recent studies suggest that epigenetics plays a crucial role in AAD. METHODS: The epigenetic regulation of histone lactylation was analyzed in the aorta of patients with aortic aneurysm and in a murine model of AAD. Histone lactylation was also studied in VSMCs treated with angiotensin II. The epigenetic pathway involving H4K16 lactylation (H4K16la) was explored in vitro and in vivo. To examine the role of H4K16la in AAD formation, mice lacking Pdk1 or Kat7 in VSMCs were created. Mice were treated with pharmacological inhibitors of Pdk1 or Kat7. The levels of blood lactate, aortic lactate, and aortic H4K16la were compared between patients with aortic aneurysm and controls. RESULTS: Histone lactylation (H4K16la) was increased in the aortic tissues of patients with AAD and mice. Enhanced histone lactylation was linked to increased pyruvate dehydrogenase kinase 1 (PDK1) transcription, which accelerated lactate production in VSMCs. A positive feedback loop was identified involving H4K16la, PDK1, and lactate; this pathway alters the metabolism and phenotype of VSMCs. KAT7 (lysine acetyltransferase 7) was found to be a histone lactyltransferase for histone lactylation in VSMCs. Genetic or pharmacological inhibition of PDK1 or KAT7 decreased AAD injury by disrupting the H4K16la/PDK1/lactate pathway. Patients with AAD have elevated lactate in blood and aortic tissues and elevated H4K16la in aortic tissues compared with control patients. CONCLUSIONS: Histone lactylation changes the metabolism and phenotype of VSMC in AAD. Inhibition of PDK1 or KAT7 may be a novel approach to treat or prevent AAD.
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