Growth/death, Regeneration and Stem cellsP60The PPARbeta agonist GW0742 protects cardiac myocytes from oxidative stress through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms

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Peroxisome proliferator-activated receptors (PPARs) (α, β and γ isoforms) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and are known to play a prominent role in the regulation of lipid metabolism and homeostasis. Emerging evidence indicates that their activation leads to cardioprotection after ischemia/reperfusion (I/R) and prevents cardiac remodelling and failure. However, the exact role of PPARs, in particular PPARβ isoform, in cardiac pathophysiology has not been defined yet. The aim of this study was to determine the effect of PPARβ activation during oxidative stress in cardiomyocytes and identify the underlying molecular mechanisms that lead to protection. Adult rat cardiomyocytes were subjected to oxidative stress (0.1 mM H2O2) in the presence or absence of PPARβ specific ligand GW0742. Cell viability, the extent of apoptosis as well as production of reactive oxygen species (ROS) were determined by flow cytometry. Activation of PPARβ inhibited ROS production and cardiac myocyte apoptosis and resulted in increased cell viability. Furthermore, heme oxygenase 1 (HMOX1), a stress-response protein was downregulated when GW0742 was present during oxidative stress. To explore further the underlying mechanisms, expression of the anti-apoptotic Bcl-2 protein and activation of metalloproteases (MMP) 2 and 9 was also determined. Decreased levels of Bcl-2, which were observed during exposure of cardiomyocytes to H2O2, were upregulated in the presence of GW0742, as determined by immunoblotting. In addition, PPARβ activation resulted in inhibition of MMP-2 and MMP-9 expression and enzymatic activity levels as determined by real time PCR and gelatin zymography, respectively. These data support the anti-oxidant, anti-apoptotic and anti-inflammatory role of PPARβ in cardiac myocytes. The underlying protective mechanisms include inhibition of ROS production, upregulation of the anti-apoptotic protein Bcl-2 and inhibition of MMP-2 and MMP-9.

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