TY - JOUR
T1 - 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
AU - Papatheodorou, Ioanna
AU - Makrecka-Kuka, Marina
AU - Kuka, Janis
AU - Liepinsh, Edgars
AU - Dambrova, Maija
AU - Lazou, Antigone
N1 - Funding Information:
The work was supported by core institutional funds and the Graduate Program “Applications of Biology” of the School of Biology, Aristotle University of Thessaloniki.
Funding Information:
The authors thank Dr Reinis Vilskersts for his assistance during ex vivo experimental procedures and Stanislava Korzh for her assistance during high resolution fluorespirometry procedures. This article is based upon work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology).
Publisher Copyright:
Copyright © 2022 Papatheodorou, Makrecka-Kuka, Kuka, Liepinsh, Dambrova and Lazou.
PY - 2022/8/15
Y1 - 2022/8/15
N2 - 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.
AB - 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.
KW - cardioprotection
KW - electron transport system
KW - fatty acid oxidation
KW - ischemia/reperfusion
KW - mitochondrial respiration
KW - PPARβ/δ
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=85136862089&partnerID=8YFLogxK
U2 - 10.3389/fendo.2022.941822
DO - 10.3389/fendo.2022.941822
M3 - Article
AN - SCOPUS:85136862089
SN - 1664-2392
VL - 13
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 941822
ER -
