PPARδ activation improves cardiac mitochondrial homeostasis in desmin deficient mice but does not alleviate systolic dysfunction

Dimitra Palioura; Kyriakos Mellidis; Konstantina Ioannidou-Kabouri; Eleftheria Galatou; Eleni-Taxiarchia Mouchtouri; Rodopi Stamatiou; Panagiotis Mavrommatis-Parasidis; Emmanuel Panteris; Aimilia Varela; Constantinos Davos; Konstantinos Drosatos; Manolis Mavroidis; Antigone Lazou

doi:10.1016/j.yjmcc.2023.08.005

PPARδ activation improves cardiac mitochondrial homeostasis in desmin deficient mice but does not alleviate systolic dysfunction

J Mol Cell Cardiol. 2023 Oct:183:27-41. doi: 10.1016/j.yjmcc.2023.08.005. Epub 2023 Aug 19.

Affiliations

¹ Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
² Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
³ Department of Botany, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
⁴ Clinical, Experimental Surgery & Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
⁵ Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
⁶ Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece. Electronic address: lazou@bio.auth.gr.

PMID: 37603971
DOI: 10.1016/j.yjmcc.2023.08.005

Abstract

Peroxisome proliferator-activated receptor (PPAR) δ is a major transcriptional regulator of cardiac energy metabolism with pleiotropic properties, including anti-inflammatory, anti-oxidative and cardioprotective action. In this study, we sought to investigate whether pharmacological activation of PPARδ via intraperitoneal administration of the selective ligand GW0742 could ameliorate heart failure and mitochondrial dysfunction that have been previously reported in a characterized genetic model of heart failure, the desmin null mice (Des^-/-). Our studies demonstrate that treatment of Des^-/- mice with the PPARδ agonist attenuated cardiac inflammation, fibrosis and cardiac remodeling. In addition, PPARδ activation alleviated oxidative stress in the failing myocardium as evidenced by decreased ROS levels. Importantly, PPARδ activation stimulated mitochondrial biogenesis, prevented mitochondrial and sarcoplasmic reticulum vacuolar degeneration and improved the mitochondrial intracellular distribution. Finally, PPARδ activation alleviated the mitochondrial respiratory dysfunction, prevented energy depletion and alleviated excessive autophagy and mitophagy in Des^-/- hearts. Nevertheless, improvement of all these parameters did not suffice to overcome the significant structural deficiencies that desmin deletion incurs in cardiomyocytes and cardiac function did not improve significantly. In conclusion, pharmacological PPARδ activation in Des^-/- hearts exerts protective effects during myocardial degeneration and heart failure by preserving the function and quality of the mitochondrial network. These findings implicate PPARδ agonists as a supplemental constituent of heart failure medications.

Keywords: Heart failure; Mitochondria; Mitochondrial biogenesis and dynamics; Mitochondrial respiration; Myocardial remodeling; Peroxisome proliferator-activated receptor δ.