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

Yu, Liming; Huang, Tao; Zhao, Jikai; Zhou, Zijun; Cao, Zijun; Chi, Yanbang; Meng, Shan; Huang, Yuting; Xu, Yinli; Xia, Lin; Jiang, Hui; Yin, Zongtao; Wang, Huishan

doi:10.1016/j.freeradbiomed.2023.11.002

Cited by 5 publications

(2 citation statements)

References 59 publications

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“…Such a phenotypic switch of vascular smooth muscle cells could be related to metabolic reprogramming. For example, metabolic reprogramming of VSMCs was suggested to play a critical role in the pathogenesis of thoracic aortic dissection involving mitochondrial ROS damage and altered mTOR signalling [ 42 ]. Further studies are needed to understand better the metabolic mechanisms underlying the phenotypic switch in VSMCs that contribute to age-dependent arterial stiffness and remodelling and to uncover the details of the metabolic reprogramming detected here as functional impairment of respiratory and glycolytic reserve associated with NAD deficiency [ 43 – 45 ].…”

Section: Discussionmentioning

confidence: 99%

Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice

Karaś,

Bar,

Pandian

et al. 2024

GeroScience

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Vascular ageing is associated with increased arterial stiffness and cardiovascular mortality that might be linked to altered vascular energy metabolism. The aim of this study was to establish a Seahorse XFe96 Analyzer-based methodology for the reliable, functional assessment of mitochondrial respiration and glycolysis in single murine aortic rings and to validate this functional assay by characterising alterations in vascular energy metabolism in aged mice. Healthy young and old C57BL/6 mice were used for the analyses. An optimised setup consisting of the Seahorse XFe96 Analyzer and Seahorse Spheroid Microplates was applied for the mitochondrial stress test and the glycolysis stress test on the isolated murine aortic rings, supplemented with analysis of NAD content in the aorta. To confirm the age-dependent stiffness of the vasculature, pulse wave velocity was measured in vivo. In addition, the activity of vascular nitric oxide synthase and vascular wall morphology were analysed ex vivo. The vascular ageing phenotype in old mice was confirmed by increased aortic stiffness, vascular wall remodelling, and nitric oxide synthase activity impairment. The rings of the aorta taken from old mice showed changes in vascular energy metabolism, including impaired spare respiratory capacity, maximal respiration, glycolysis, and glycolytic capacity, as well as a fall in the NAD pool. In conclusion, optimised Seahorse XFe96-based analysis to study energy metabolism in single aortic rings of murine aorta revealed a robust impairment of functional vascular respiratory and glycolytic capacity in old mice linked to NAD deficiency that coincided with age-related aortic wall remodelling and stiffness.

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Section: Discussionmentioning

confidence: 99%

Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice

Karaś,

Bar,

Pandian

et al. 2024

GeroScience

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“…Differentially expressed genes (DEGs) were identified using the ‘limma’ package (absolute Log 2 FC value greater than 0.263, a p ‐value <0.05). 21 We performed GO and KEGG pathway enrichment analyses for these DEGs using the Metascape bioinformatics resources ( http://metascape.org , version 3.5.20230501).…”

Section: Methodsmentioning

confidence: 99%

Berberine ameliorates chronic intermittent hypoxia‐induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling

Zhou,

Zhao,

Huang

et al. 2024

J Cellular Molecular Medi

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Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH‐induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH‐induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno‐associated virus 9 (AAV9) carrying SIRT6 or SIRT6‐specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK‐FOXO3a signalling. BBR dose‐dependently ameliorated cardiac injury in CIH‐induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6‐specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6‐AMPK‐FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1‐Parkin‐mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH‐induced cardiac dysfunction. BBR attenuates CIH‐induced myocardial injury by improving mitochondrial biogenesis and PINK1‐Parkin‐dependent mitophagy via the SIRT6‐AMPK‐FOXO3a signalling pathway.

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Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway

Huang,

Zhao,

Zhou

et al. 2025

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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

Cited by 5 publications

References 59 publications

Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice

Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice

Berberine ameliorates chronic intermittent hypoxia‐induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling

Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway

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