Activation of PPARβ/δ protects cardiac myocytes from oxidative stress-induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases

Abstract

Heart failure still remains one of the leading causes of morbidity and mortality worldwide. A major contributing factor is reactive oxygen/nitrogen species (RONS) overproduction which is associated with cardiac remodeling partly through cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily and have been implicated in cardioprotection. However, the molecular mechanisms are largely unexplored. In this study we sought to investigate the potential beneficial effects evoked by activation of PPARβ/δ under the setting of oxidative stress induced by H2O2 in adult rat cardiac myocytes. The selective PPARβ/δ agonist GW0742 inhibited the H2O2-induced apoptosis and increased cell viability. In addition, generation of RONS was attenuated in cardiac myocytes in the presence of PPARβ/δ agonist. These effects were abolished in the presence of the PPARβ/δ antagonist indicating that the effect was through PPARβ/δ receptor activation. Treatment with PPARβ/δ agonist was also associated with attenuation of caspase-3 and PARP cleavage, upregulation of anti-apoptotic Bcl-2 and concomitant downregulation of pro-apoptotic Bax. In addition, activation of PPARβ/δ inhibited the oxidative-stress-induced MMP-2 and MMP-9 mRNA upregulation. It is concluded that PPARβ/δ activation exerts a cytoprotective effect in adult rat cardiac myocytes subjected to oxidative stress via inhibition of oxidative stress, MMP expression, and apoptosis. Our data suggest that the novel connection between PPAR signaling and MMP down-regulation in cardiac myocytes might represent a new target for the management of oxidative stress-induced cardiac dysfunction.

Cardiac metabolism — A promising therapeutic target for heart failure

“…Selective PPARβ/δ agonists have also been shown to have beneficial cytoprotective effects in rat cardiomyocytes subjected to oxidative stress (Barlaka, et al, 2015). To date there are no clinical trials that have studied PPARα agonists as specific metabolic therapies in HF.…”

Effects of <b><i>Aloe</i></b> Sterol Supplementation on Skin Elasticity, Hydration, and Collagen Score: A 12-Week Double-Blind, Randomized, Controlled Trial

“…PPAR regulate the expression of genes that are mostly involved in lipid and carbohydrate metabolism, energy production, and anti-inflammation activities [11]. Barlaka et al [12] reported that a novel connection between PPAR signaling and downregulation of matrix metalloproteinases (MMP) in cardiac myocytes may be involved in the management of oxidative stress-induced cardiac dysfunction. Our recent study demonstrated that Aloe sterol significantly prevented an increase in the total protein expression of MMP-2 (active and pro) and MMP-9 (active and pro) in ultraviolet B (UVB)-irradiated mice [13].…”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…Modulation of Bcl-2 family proteins (Bcl-2 and Bax) and attenuation of PPAR and caspase-3 cleavage were shown in adult cardiac myocytes pretreated with PPARb/d stress [104]. In the same study, transcriptional control of matrix metalloproteases (MMPs) resulting in the inhibition of apoptosis was also suggested.…”

“…Specifically, cardiomyocytes-restricted PPARb/d deletion resulted in increased oxidative stress in the heart, mediated from Cu/Zn-SOD and Mn-SOD downregulation [102], while cardiomyocyte-restricted overexpression of a constitutively active PPARb/d enhanced antioxidant capacity resulting in improved cardiac performance under left ventricular pressure overload [103]. A recent in vitro study demonstrated suppression of ROS generation and oxidative stress in cultured cardiac myocytes treated with a PPARb/d agonist, implicating catalase upregulation [104]. Furthermore, PPARb/d has been suggested to inhibit ROS generation through the inhibition of NADPH oxidases in vascular smooth muscle cells exposed to angiotensin II [105].…”