2. Academic Validation
  3. ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

  • Acta Pharm Sin B. 2024 Jul;14(7):3027-3048. doi: 10.1016/j.apsb.2024.03.008.
Mengdie Dong 1,  Yunjia Zhang 2,  Minghong Chen 2,  Yongkang Tan 2,  Jiao Min 2,  Xian He 2,  Fuhao Liu 3,  Jiaming Gu 2,  Hong Jiang 2,  Longbin Zheng 2 4,  Jiajing Chen 2,  Quanwen Yin 2,  Xuesong Li 2,  Xiang Chen 2,  Yongfeng Shao 5,  Yong Ji 6 7,  Hongshan Chen 1 8 9
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, and Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing 211166, China.
  • 2 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 3 Department of Clinical Medicine, Nanjing Medical University TIANYUAN Honors School, Nanjing Medical University, Nanjing 211166, China.
  • 4 Department of Anesthesiology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 5 Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 211166, China.
  • 6 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, School of Pharmacy, the Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Nanjing 211166, China.
  • 7 National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Key Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, NHC Key Laboratory of Cell Transplantation, the Central Laboratory of the First Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
  • 8 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 9 Department of Cardiology, Huai'an First People's Hospital Affiliated with Nanjing Medical University, Huai'an 223399, China.
PMID: 39027248 DOI: 10.1016/j.apsb.2024.03.008
Abstract

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients' arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on apoE KO Asf1a ECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and Epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

Keywords

ASF1A; Atherosclerosis; Endothelial dysfunction; Endothelial-to-mesenchymal transition; Epigenetic; Histone lactylation; Lactate; SNAI1.

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