β-羟丁酸通过组蛋白赖氨酸β-羟丁酸化CPT1A促进心肌梗死后缺氧内皮细胞的内稳态

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC: Basic to Translational Science Pub Date : 2025-05-01 DOI:10.1016/j.jacbts.2024.11.004

Zhaoyue Li MD, PhD , Yutong Guo MD , Jie Xiong MD , Liyan Bai MD , Hao Tang MD, PhD , Bo Wang MD , Bingchen Guo MD , Yi Qiu MD , Guanghui Li MD , Manyu Gong MD, PhD , Lin Lv MD, PhD , Zengxiang Dong MD, PhD , Yingfeng Tu MD, PhD

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引用次数: 0

摘要

心肌梗死（MI）启动一个强大的血管生成反应至关重要的组织修复。β-羟基丁酸酯（BHB）是一种必需的循环代谢物，其在病理条件下血管生成中的作用尚不清楚。我们评估了114例心肌梗死患者的冠状动脉侧枝循环，并研究了其与血清BHB水平的相关性。高BHB水平被发现与更好的侧支循环相关。此外，BHB在体内和体外均促进心肌梗死后血管生成。在机制上，BHB通过增加与血管生成相关基因转录激活相关的H3K9bhb水平，并增强与这些基因相关位点的染色质可及性来调节缺氧内皮细胞的表观遗传景观。通过RNA测序、靶点切割和标记、转座酶可及染色质测序等综合分析，确定肉碱棕榈酰转移酶1a是促血管生成的关键靶点。因此，补充BHB营养可能是缺血性心脏病的一种有希望的治疗策略，具有很高的临床转化潜力。

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β-Hydroxybutyrate Facilitates Homeostasis of Hypoxic Endothelial Cells After Myocardial Infarction via Histone Lysine β-Hydroxybutyrylation of CPT1A

Myocardial infarction (MI) initiates a robust angiogenic response crucial for tissue repair. β-hydroxybutyrate (BHB) is an essential circulating metabolite, and its role in angiogenesis under pathological conditions remains unclear. We evaluated the coronary collateral circulation in 114 patients with MI and investigated its correlation with serum BHB levels. High BHB levels were found to correlate with better collateral circulation. Moreover, BHB promotes angiogenesis post-MI in vivo and in vitro. Mechanistically, BHB modulates the epigenetic landscape in hypoxic endothelial cells by increasing H3K9bhb levels associated with the transcriptional activation of angiogenesis-related genes and enhancing chromatin accessibility at loci associated with these genes. The integrated analysis of RNA sequencing, cleavage under targets and tagmentation, and assay for transposase-accessible chromatin with sequencing identified carnitine palmitoyltransferase 1a as a key proangiogenic target. Thus, BHB nutritional supplementation may represent a promising therapeutic strategy for ischemic heart disease, with high potential for clinical translation.

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.