Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME−/−/ApoE−/− mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.

Glycated hemoglobin A1c (HbA1c) has been recognized as a predictor of cardiovascular events. However, the relationship between HbA1c and coronary artery disease (CAD) in the Chinese population has yet to be systematically explored. In addition, factors associated with HbA1c were generally analyzed linearly, thereby failing to appreciate more complex nonlinear associations. The study aimed to evaluate the relationship between the HbA1c value and the presence and severity of coronary artery stenosis. A total of 7192 consecutive patients who underwent coronary angiography were enrolled. Their biological parameters, including HbA1c, were measured. The severity of coronary stenosis was evaluated using Gensini score. After correcting for baseline confounding factors, a multivariate logistic regression analysis was used to evaluate the relationship between HbA1c and CAD severity. Restricted cubic splines were applied to explore the relation of HbA1c with the presence of CAD, myocardial infarction (MI), and the severity of coronary lesions. HbA1c was significantly associated with the presence and severity of CAD in patients without diagnosed diabetes (odds ratio: 1.306, 95% confidence interval: 1.053–1.619, p = 0.015). Spline analysis showed a U-shaped association of HbA1c with the presence of MI. Both HbA1c > 7.2% and HbA1c < 5.7% were associated with the presence of MI. In conclusion, HbA1c value was highly associated with the severity of coronary artery stenosis in the whole study population, and in CAD patients without diagnosed diabetes. Compared with patients with HbA1c levels between 6.0% and 7.0%, HbA1c < 5.7% and HbA1c > 7.2% were associated with higher presence of MI.