BCAT2 enzyme identified as a target for diabetic foot recovery

Diabetic macrovascular complications are the main cause of death and disability in diabetes patients, of which vascular calcification is one of the key pathological mechanisms. Calcification in atherosclerotic plaque can cause stiffness and decreased compliance of the vascular wall, and induce atherosclerotic plaque rupture, which increases the risk of acute cardiovascular events.

Compared with non-diabetic patients, patients with diabetes have atherosclerotic plaques in the coronary artery with a larger necrotic core and extensive calcification. Vascular calcification is an active process involving osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMCs). However, the molecular mechanisms underlying vascular calcification in diabetic atherosclerotic plaques have not been fully elucidated, and no effective interventions have been identified.

Research progress

In order to identify the intervention targets for vascular calcification in diabetic atherosclerotic plaques, Prof. Zhongqun Wang's team at the Department of Cardiology, Affiliated Hospital of Jiangsu University has performed spatial metabolomics and single-cell transcriptomics analyses on the anterior tibial arteries of diabetic foot amputations.

Results indicated that the catabolism of branched-chain amino acids (BCAAs) was enhanced and the expression of BCAT2 (a key metabolic enzyme in the BCAA catabolic pathway) in VSMCs was increased in the calcified anterior tibial arteries of patients with diabetic foot undergoing amputation.

To investigate the biological role and mechanism of BCAT2 in intraplaque calcification in diabetes, the researchers generated apolipoprotein E (ApoE) and VSMCs-specific BCAT2 double knockout mice (ApoE^⁻/⁻/BCAT2^ΔSMC). These mice were then subjected to analysis in a diabetic atherosclerosis calcification model. Experimental results demonstrated that VSMC-specific BCAT2 knockout mice exhibited a significant reduction in vascular calcification severity, decreased calcium salt deposition, and suppressed osteogenic phenotypic transition of vascular smooth muscle cells.

RNA sequencing revealed that the expression of Runx2 was markedly downregulated in vascular smooth muscle cells (VSMCs) following BCAT2 knockout. Further analyses of chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) data demonstrated that the level of histone H3 lysine 23 propionylation (H3K23pr) in the promoter region of RUNX2 was significantly decreased after BCAT2 knockout, whereas it was upregulated upon BCKA supplementation. Moreover, silencing of RUNX2 substantially abrogated the regulatory effect of the BCAT2-BCKA axis on the osteogenic differentiation of VSMCs.

Taken together, this study is the first to reveal the regulatory role of BCAT2-mediated branched-chain amino acid (BCAA) catabolism in vascular smooth muscle cells (VSMCs) in the development of intraplaque calcification in diabetic atherosclerosis. It further clarifies the mechanism by which the BCAT2-BCKA-histone propionylation axis regulates the osteogenic transdifferentiation of VSMCs and the progression of intraplaque calcification in diabetes. Furthermore, this study provides important experimental evidence for the precise prevention and treatment of intraplaque calcification in diabetes based on the targeted inhibition of BCAT2(Fig 1).

Future prospects

This study is the first to identify the remodeling of branched-chain amino acid (BCAA) catabolism in diabetic calcified blood vessels. It further elucidates the role and regulatory mechanism of BCAT2-mediated BCAA catabolism in vascular smooth muscle cells (VSMCs) in the development of intraplaque calcification in diabetic atherosclerosis. In the future, targeted inhibition of BCAT2 is expected to provide a theoretical basis for the precise treatment of intraplaque calcification in diabetes.