Effect of extracellular matrix stiffness on efficacy of Dapagliflozin for diabetic cardiomyopathy

作者：Tong Zhu, Zhaoyang Ye, Jingjing Song, Junjie Zhang, Yuxiang Zhao, Feng Xu, Jun Wang, Xin Huang, Bin Gao, Fei Li · 发表于：Cardiovascular Diabetology · 年份：2024 · DOI：10.1186/s12933-024-02369-x · 被引用次数：13 · 研究领域：Cardiovascular Function and Risk Factors、Elasticity and Material Modeling、Cardiac Fibrosis and Remodeling

Abstract Background Extracellular matrix (ECM) stiffness is closely related to the progress of diabetic cardiomyopathy (DCM) and the response of treatment of DCM to anti-diabetic drugs. Dapagliflozin (Dapa) has been proven to have cardio-protective efficacy for diabetes and listed as the first-line drug to treat heart failure. But the regulatory relationship between ECM stiffness and treatment efficacy of Dapa remains elusive. Materials and methods This work investigated the effect of ECM stiffness on DCM progression and Dapa efficacy using both in vivo DCM rat model and in vitro myocardial cell model with high glucose injury. First, through DCM rat models with various levels of myocardial injury and administration with Dapa treatment for four weeks, the levels of myocardial injury, myocardial oxidative stress, expressions of AT 1 R (a mechanical signal protein) and the stiffness of myocardial tissues were obtained. Then for mimicking the stiffness of myocardial tissues at early and late stages of DCM, we constructed cell models through culturing H9c2 myocardial cells on the polyacrylamide gels with two stiffness and exposed to a high glucose level and without/with Dapa intervention. The cell viability, reactive oxygen species (ROS) levels and expressions of mechanical signal sensitive proteins were obtained. Results The DCM progression is accompanied by the increased myocardial tissue stiffness, which can synergistically exacerbate myocardial cell injury with high glucose. D...