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Diabetic macrovascular complications are nan main origin of decease and disablement successful glucosuria patients, of which vascular calcification is 1 of nan cardinal pathological mechanisms. Calcification successful atherosclerotic plaque tin origin stiffness and decreased compliance of nan vascular wall, and induce atherosclerotic plaque rupture, which increases nan consequence of acute cardiovascular events.
Compared pinch non-diabetic patients, patients pinch glucosuria person atherosclerotic plaques successful nan coronary artery pinch a larger necrotic halfway and extended calcification. Vascular calcification is an progressive process involving osteoblastic differentiation and mineralization of vascular soft musculus cells (VSMCs). However, nan molecular mechanisms underlying vascular calcification successful diabetic atherosclerotic plaques person not been afloat elucidated, and nary effective interventions person been identified.
Research progress
In bid to place nan involution targets for vascular calcification successful diabetic atherosclerotic plaques, Prof. Zhongqun Wang's squad astatine nan Department of Cardiology, Affiliated Hospital of Jiangsu University has performed spatial metabolomics and single-cell transcriptomics analyses connected nan anterior tibial arteries of diabetic ft amputations.
Results indicated that nan catabolism of branched-chain amino acids (BCAAs) was enhanced and nan look of BCAT2 (a cardinal metabolic enzyme successful nan BCAA catabolic pathway) successful VSMCs was accrued successful nan calcified anterior tibial arteries of patients pinch diabetic ft undergoing amputation.
To analyse nan biologic domiciled and system of BCAT2 successful intraplaque calcification successful diabetes, nan researchers generated apolipoprotein E (ApoE) and VSMCs-specific BCAT2 double knockout mice (ApoE⁻/⁻/BCAT2ΔSMC). These mice were past subjected to study successful a diabetic atherosclerosis calcification model. Experimental results demonstrated that VSMC-specific BCAT2 knockout mice exhibited a important simplification successful vascular calcification severity, decreased calcium brackish deposition, and suppressed osteogenic phenotypic modulation of vascular soft musculus cells.
RNA sequencing revealed that nan look of Runx2 was markedly downregulated successful vascular soft musculus cells (VSMCs) pursuing BCAT2 knockout. Further analyses of chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative polymerase concatenation guidance (ChIP-qPCR) information demonstrated that nan level of histone H3 lysine 23 propionylation (H3K23pr) successful nan promoter region of RUNX2 was importantly decreased aft BCAT2 knockout, whereas it was upregulated upon BCKA supplementation. Moreover, silencing of RUNX2 substantially abrogated nan regulatory effect of nan BCAT2-BCKA axis connected nan osteogenic differentiation of VSMCs.
Taken together, this study is nan first to uncover nan regulatory domiciled of BCAT2-mediated branched-chain amino acerb (BCAA) catabolism successful vascular soft musculus cells (VSMCs) successful nan improvement of intraplaque calcification successful diabetic atherosclerosis. It further clarifies nan system by which nan BCAT2-BCKA-histone propionylation axis regulates nan osteogenic transdifferentiation of VSMCs and nan progression of intraplaque calcification successful diabetes. Furthermore, this study provides important experimental grounds for nan precise prevention and curen of intraplaque calcification successful glucosuria based connected nan targeted inhibition of BCAT2(Fig 1).
Future prospects
This study is nan first to place nan remodeling of branched-chain amino acerb (BCAA) catabolism successful diabetic calcified humor vessels. It further elucidates nan domiciled and regulatory system of BCAT2-mediated BCAA catabolism successful vascular soft musculus cells (VSMCs) successful nan improvement of intraplaque calcification successful diabetic atherosclerosis. In nan future, targeted inhibition of BCAT2 is expected to supply a theoretical ground for nan precise curen of intraplaque calcification successful diabetes.
Source:
Journal reference:
Zhang, L., et al. (2026). Vascular Smooth Muscle Cell-Specific BCAT2 Deficiency Attenuates Diabetic Atherosclerotic Calcification via Histone Propionylation. Research. DOI: 10.34133/research.1052. https://spj.science.org/doi/10.34133/research.1052.
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