Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy

Yang Shen; Xiaojie Peng; Haizhe Ji; Wei Gong; Hang Zhu; Jin Wang

doi:10.1016/j.ijbiomac.2023.126116

Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy

Int J Biol Macromol. 2023 Oct 1:250:126116. doi: 10.1016/j.ijbiomac.2023.126116. Epub 2023 Aug 2.

Authors

Yang Shen¹, Xiaojie Peng², Haizhe Ji³, Wei Gong⁴, Hang Zhu⁵, Jin Wang⁶

Affiliations

¹ 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.
² 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.
³ Faculty of medicine, Dalian university of technology, Dalian, China.
⁴ Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China; The Third School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong, China. Electronic address: gongwei@smu.edu.cn.
⁵ 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. Electronic address: zhuhang301@outlook.com.
⁶ Department of Vascular Medicine, Peking University Shougang Hospital, Beijing 100144, China. Electronic address: nkuwangjin@163.com.

PMID: 37541471
DOI: 10.1016/j.ijbiomac.2023.126116

Abstract

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^CKO) and FUNDC1 knockout (FUNDC1^CKO) 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.

Keywords: CRS-4; Dapagliflozin; FUNDC1; Mitochondria; PKM2; PP1.