Pharmacological activation of PPARβ/δ preserves mitochondrial respiratory function in ischemia/reperfusion via stimulation of fatty acid oxidation-linked respiration and PGC-1α/NRF-1 signaling

Myocardial ischemia/reperfusion (I/R) injury leads to significant impairment of cardiac function and remains the leading cause of morbidity and mortality worldwide. Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) confers cardioprotection via pleiotropic effects including antio...

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Veröffentlicht in:Frontiers in endocrinology (Lausanne) Jg. 13; S. 941822
Hauptverfasser: Papatheodorou, Ioanna, Makrecka-Kuka, Marina, Kuka, Janis, Liepinsh, Edgars, Dambrova, Maija, Lazou, Antigone
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Frontiers Media S.A 15.08.2022
Schlagworte:
cardioprotection
electron transport system
Endocrinology
fatty acid oxidation
ischemia/reperfusion
mitochondrial respiration
ROS
ISSN:1664-2392, 1664-2392
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Zusammenfassung:Myocardial ischemia/reperfusion (I/R) injury leads to significant impairment of cardiac function and remains the leading cause of morbidity and mortality worldwide. Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) confers cardioprotection via pleiotropic effects including antioxidant and anti-inflammatory actions; however, the underlying mechanisms are not yet fully elucidated. The aim of this study was to investigate the effect of PPARβ/δ activation on myocardial mitochondrial respiratory function and link this effect with cardioprotection after ischemia/reperfusion (I/R). For this purpose, rats were treated with the PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo . Mitochondrial respiration and ROS production rates were determined using high-resolution fluororespirometry. Activation of PPARβ/δ did not alter mitochondrial respiratory function in the healthy heart, however, inhibition of PPARβ/δ reduced fatty acid oxidation (FAO) and complex II-linked mitochondrial respiration and shifted the substrate dependence away from succinate-related energy production and towards NADH. Activation of PPARβ/δ reduced mitochondrial stress during in vitro anoxia/reoxygenation. Furthermore, it preserved FAO-dependent mitochondrial respiration and lowered ROS production at oxidative phosphorylation (OXPHOS)-dependent state during ex vivo I/R. PPARβ/δ activation was also followed by increased mRNA expression of components of FAO -linked respiration and of transcription factors governing mitochondrial homeostasis (carnitine palmitoyl transferase 1b and 2-CPT-1b and CPT-2, electron transfer flavoprotein dehydrogenase -ETFDH, peroxisome proliferator-activated receptor gamma co-activator 1 alpha- PGC-1α and nuclear respiratory factor 1-NRF-1). In conclusion, activation of PPARβ/δ stimulated both FAO-linked respiration and PGC-1α/NRF -1 signaling and preserved mitochondrial respiratory function during I/R. These effects are associated with reduced infarct size.
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Reviewed by: Sruti Shiva, University of Pittsburgh, United States; Pasquale Pagliaro, University of Turin, Italy; Gerd Heusch, University of Duisburg-Essen, Germany; Puneet Randhawa, University of Central Florida, United States
This article was submitted to Cellular Endocrinology, a section of the journal Frontiers in Endocrinology
Edited by: Guillermo Romero, University of Pittsburgh, United States
ISSN:1664-2392
1664-2392
DOI:10.3389/fendo.2022.941822