Cardioprotective Effects of PPARβ/δ Activation against Ischemia/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production.

Ioanna Papatheodorou,Georgios-Dimitrios Panagiotidis,Táňa Ravingerová,Antigone Lazou,Eleftheria Galatou

doi:10.3390/ijms22126399

Ioanna Papatheodorou, Georgios-Dimitrios Panagiotidis + Show 3 more

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https://doi.org/10.3390/ijms22126399

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Abstract

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARβ/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARβ/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARβ/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARβ/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARβ/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.

Highlights

Ischemic heart disease and its most common manifestation acute myocardial infarction (MI) and the development of heart failure, remains a leading cause of death and disability worldwide
We propose a new mechanism that implicates a coordinated action of peroxisome proliferator activated receptor β/δ (PPARβ/δ) transcriptional activation on both antioxidant enzymes and mitochondrial function to ameliorate oxidative stress and maintain energy production, resulting in the alleviation of I/R injury
Pretreatment of animals with the PPARβ/δ ligand GW0742 led to a significant increase in post-ischemic LVDP recovery (Figure 1A) which appeared higher by almost 52%

Summary

Introduction

Ischemic heart disease and its most common manifestation acute myocardial infarction (MI) and the development of heart failure, remains a leading cause of death and disability worldwide. The only available treatment of choice up to date is timely and effective myocardial reperfusion. Novel therapeutic strategies focus on reducing the size of the myocardial infarction while preventing the development of I/R injury and heart failure by enhancing processes aiming at preserving cardiac function. Despite intense efforts to address post-I/R cardiac injury and dysfunction and the identification of important regulators of cardiac homeostasis with potential cardioprotective properties, translation of cardioprotection to clinical practice has proven difficult. Potential reasons may include the complexity of mechanisms underlying I/R or the requirement for synergistic multitarget effects for optimal cardioprotection [2,3]

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