Shen Yang, Peng Xiaojie, Ji Haizhe, Gong Wei, Zhu Hang, Wang Jin
Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou, 510006; Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.
Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China; The Third School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China; Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou city, Guangdong province, China.
Int J Biol Macromol. 2023 Oct 1;250:126116. doi: 10.1016/j.ijbiomac.2023.126116. Epub 2023 Aug 2.
Dapagliflozin (DAPA) confers significant protection against heart and kidney diseases. However, whether DAPA can alleviate type 4 cardiorenal syndrome (CRS-4)-related cardiomyopathy remains unclear. We tested the hypothesis that DAPA attenuates CRS-4-related myocardial damage through pyruvate kinase isozyme M2 (PKM2) induction and FUN14 domain containing 1 (FUNDC1)-related mitophagy. Cardiomyocyte-specific PKM2 knockout (PKM2) and FUNDC1 knockout (FUNDC1) mice were subjected to subtotal (5/6) nephrectomy to establish a CRS-4 model in vivo. DAPA enhanced PKM2 expression and improved myocardial function and structure in vivo, and this effect was abrogated by PKM2 knockdown. A significant improvement in mitochondrial function was observed in HL-1 cells exposed to sera from DAPA-treated mice, as featured by increased ATP production, decreased mtROS production, improved mitochondrial membrane potential, preserved mitochondrial complex activity, and reduced mitochondrial apoptosis. DAPA restored FUNDC1-dependent mitophagy through post-transcriptional dephosphorylation in a manner dependent on PKM2 whereas ablation of FUNDC1 abolished the defensive actions of DAPA on myocardium and mitochondria under CRS-4. Co-IP and molecular docking assays indicated that PKM2 directly interacted with protein phosphatase 1 (PP1) and FUNDC1, leading to PP1-mediated FUNDC1 dephosphorylation. These results suggest that DAPA attenuates CRS-4-related cardiomyopathy through activating the PKM2/PP1/FUNDC1-mitophagy pathway.
达格列净（DAPA）对心脏和肾脏疾病具有显著的保护作用。然而，DAPA是否能减轻4型心肾综合征（CRS-4）相关的心肌病仍不清楚。我们验证了这样一个假设，即DAPA通过诱导丙酮酸激酶同工酶M2（PKM2）和与含FUN14结构域1（FUNDC1）相关的线粒体自噬来减轻CRS-4相关的心肌损伤。对心肌细胞特异性PKM2基因敲除（PKM2-/-）和FUNDC1基因敲除（FUNDC1-/-）小鼠进行次全（5/6）肾切除术，以在体内建立CRS-4模型。DAPA增强了PKM2的表达，并改善了体内心肌功能和结构，而PKM2基因敲低则消除了这种作用。在暴露于DAPA处理小鼠血清的HL-1细胞中观察到线粒体功能有显著改善，其特征为ATP生成增加、线粒体活性氧生成减少、线粒体膜电位改善、线粒体复合物活性维持以及线粒体凋亡减少。DAPA通过依赖PKM2的转录后去磷酸化作用恢复了FUNDC1依赖的线粒体自噬，而FUNDC1的缺失则消除了DAPA在CRS-4条件下对心肌和线粒体的保护作用。免疫共沉淀和分子对接实验表明，PKM2直接与蛋白磷酸酶1（PP1）和FUNDC1相互作用，导致PP1介导的FUNDC1去磷酸化。这些结果表明，DAPA通过激活PKM2/PP1/FUNDC1-线粒体自噬途径减轻CRS-4相关的心肌病。
