Empagliflozin attenuates coronary atherosclerosis by promoting the differentiation of pericoronary adipose-derived stem cells
S Shi, X Y Ding, Y Y YaoAbstract
Background
Epicardial adipose tissue (EAT) is visceral fat located between the myocardium and visceral pericardium. Without an anatomical barrier, EAT influences cardiac and vascular function through metabolic and paracrine pathways. Pathological alterations in EAT volume and function are implicated in the progression of various cardiovascular diseases. Clinical evidence shows that type 2 diabetes mellitus (T2DM) alters EAT volume and is a recognized risk factor for coronary atherosclerosis (CAS). Accumulating evidence suggests that T2DM may mediates the development of CAS via EAT; however, its mechanism remains unclear.
Purpose
This study aimed to investigate whether T2DM deteriorates coronary atherosclerotic lesions through its effect on adipose-derived stem cells (ADSCs) and explored its molecular mechanism.
Methods
A total of 480 chronic total occlusion (CTO) patients were enrolled and divided into two groups based on the presence of T2DM. Baseline clinical characteristics, medical history, and imaging data were collected. Computed tomography (CT) was used to quantify EAT volume, and the Gensini score was applied to assess the severity of CAS. Logistic regression was used to identify risk factors and multiple linear regression to analyze correlations between significantly different variables. Single-nucleus RNA sequencing (snRNA-seq) was applied to characterize SLC5A2 expression across populations and cell types.Human adipose-derived stem cells (ADSCs) were treated with palmitic acid and glucose to establish a diabetic model in vitro, then induced to adipogenic differentiation. The mRNA and protein levels of PPARγ, C/EBPα, IL-6 and IL-8 were quantified.
Results
Of a total of 480 patients enrolled , 198 were T2DM patients.EAT volume and coronary atherosclerosis severity were significantly higher in the T2DM group than in the non-T2DM group. After adjusting for confounders, EAT volume remained an independent risk factor for coronary atherosclerosis severity. Subgroup analysis within the T2DM group revealed that 45 patients treated with sodium-glucose cotransporter 2 (SGLT-2) inhibitors had lower EAT volume and less severe coronary atherosclerotic lesions compared to controls. SnRNA-seq of human EAT showed elevated SLC5A2 expression in patients with coronary artery disease (CAD) and T2DM, particularly in adipocytes, where expression was significantly upregulated compared to non-diabetic controls. In vitro, ADSCs-derived adipocytes in the diabetic model group exhibited enhanced adipogenic capacity and increased expression of senescence- and inflammation-related genes. All these abnormalities were ameliorated by empagliflozin treatment.
Conclusion
This study demonstrates that T2DM modulates coronary atherosclerotic lesion severity by altering the differentiation phenotype of adipose-derived stem cells, revealing a novel mechanism underlying T2DM-related atherosclerosis.Fig.1