SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes induced by type 2 diabetes

作者：Yun Wen, Xiaofang Zhang, Han Liu, Haowen Ye, Ruxin Wang, Caixia Ma, Tianqi Duo, Jiaxin Wang, Xian Yang, Meixin Yu, Ying Wang, Liangyan Wu, Yongting Zhao, Lihong Wang · 发表于：Cardiovascular Diabetology · 年份：2024 · DOI：10.1186/s12933-024-02520-8 · 被引用次数：26 · 研究领域：Cardiovascular Function and Risk Factors、Lipid metabolism and disorders、Congenital heart defects research

BACKGROUND: Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. METHODS: To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardio...