Salvianolic acid A regulates pyroptosis of endothelial cells via directly targeting PKM2 and ameliorates diabetic atherosclerosis

• DOI: 10.3389/fphar.2022.1009229
• Publication Date: 2022-11-08T07:31:52Z
• Authors: Ji Zhu; Hang Chen; Yifei Le; Jianan Guo; Zhijun Liu; Xiaobing Dou; Dezhao Lu
• Keywords: Pyroptosis; PKM2

Rescuing endothelial cells from pyroptotic cell death emerges as a potential therapeutic strategy to combat diabetic atherosclerosis. Salvianolic acid A (SAA) is major water-soluble phenolic in the Salvia miltiorrhiza Bunge, which has been used traditional Chinese medicine (TCM) and health food products for long time. This study investigated whether SAA-regulated pyruvate kinase M2 (PKM2) functions protect cells. In streptozotocin (STZ)-induced ApoE −/− mice subjected Western diet, SAA attenuated atherosclerotic plaque formation inhibited pathological changes aorta. addition, significantly prevented NLRP3 inflammasome activation pyroptosis of aortic sinus or those exposed high glucose. Mechanistically, PKM2 was verified be main target SAA. We further revealed that directly interacts with at its activator pocket, inhibits phosphorylation Y105, hinders nuclear translocation PKM2. Also, consistently decreased glucose-induced overproduction lactate partially lactate-dependent PKR (a regulator inflammasome). Further assay on Phenylalanine (PKM2 activity inhibitor) proved exhibits function dependently regulation. Furthermore, an c16 (inhibitor activity) co-phenylalanine demonstrated regulation phosphorylated drives PKM2-dependent modulation pyroptosis. Therefore, this article reports novel atherosclerosis, provides important insights into immunometabolism reprogramming cardiovascular disease complications therapy.