2. Academic Validation
  3. Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation

Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation

  • Free Radic Biol Med. 2023 Nov 11:S0891-5849(23)01095-X. doi: 10.1016/j.freeradbiomed.2023.11.002.
Liming Yu 1,  Tao Huang 1,  Jikai Zhao 1,  Zijun Zhou 1,  Zijun Cao 2,  Yanbang Chi 3,  Shan Meng 4,  Yuting Huang 1,  Yinli Xu 1,  Lin Xia 1,  Hui Jiang 1,  Zongtao Yin 1,  Huishan Wang 5
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
  • 2 Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, PR China.
  • 3 Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China.
  • 4 Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China; Graduate School, Jinzhou Medical University, Jinzhou, Liaoning, 121001, PR China.
  • 5 Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning, 110016, PR China. Electronic address: huishanw@126.com.
PMID: 37956909 DOI: 10.1016/j.freeradbiomed.2023.11.002
Abstract

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of Amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial Reactive Oxygen Species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR Activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug target for the prevention and treatment of TAD.

Keywords

BCKDHA; BCKDK; Branched-chain amino acid; Thoracic aortic dissection; Vascular smooth muscle cell; mTOR.

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