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 (PKM2CKO) and FUNDC1 knockout (FUNDC1CKO) 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: International Journal of Biological Macromolecules
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.