Chambers Jordan M, Croteau Dominique, Pimentel David R, Gower Adam C, Panagia Marcello, Baka Tomas, Qin Fuzhong, Luptak Ivan, Colucci Wilson S
Cardiovascular Medicine Section and Myocardial Biology Unit, and the Clinical and Translational Institute, Boston University School of Medicine, Boston, MA, United States of America.
J Mol Cell Cardiol Plus. 2025 Apr 9;12:100296. doi: 10.1016/j.jmccpl.2025.100296. eCollection 2025 Jun.
Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear.
Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq.
Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow).
From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis - all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU.
The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.
线粒体功能障碍，伴随三磷酸腺苷（ATP）生成减少和活性氧（ROS）释放增加，是衰竭心脏的一个标志。尽管已表明钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可改善衰竭心脏的心肌代谢，且与糖尿病无关，但其对线粒体的影响尚不清楚。
我们的目标是测试SGLT2抑制剂依格列净对心肌线粒体基因表达和功能以及从因心脏特异性过表达Gαq而患扩张型心肌病的非糖尿病小鼠分离出的线粒体的影响。
4周龄的Gαq小鼠和野生型（WT）同窝小鼠，在有或没有添加到食物中的SGLT2抑制剂依格列净（ERTU，0.5mg/g食物）的情况下，接受16周的治疗。
从第4周开始至第20周，Gαq小鼠出现进行性心脏肥大、扩张、收缩功能障碍、心肌细胞凋亡和间质纤维化，而ERTU治疗可预防所有这些情况。从Gαq小鼠分离出的心脏线粒体，其最大ATP生成减少，ROS释放增加，而ERTU可使这两者恢复正常。在从Gαq小鼠分离出的跳动心脏中，通过磷核磁共振波谱法同时测量的收缩储备和高能磷酸盐减少——而ERTU可使两者均得到改善。在Gαq小鼠中，ERTU可逆转对氧化磷酸化和脂肪酸代谢心肌基因程序的显著抑制。
SGLT2抑制剂ERTU纠正了氧化磷酸化和脂肪酸代谢心肌基因程序的表达，并与ATP生成增加、线粒体ROS释放减少以及线粒体功能障碍对心肌结构和功能影响的改善相关联。
