Involvement of Nuclear Receptors PPAR-α, PPAR-γ, and the Transcription Factor Nrf2 in Cellular Protection Against Oxidative Stress Induced by Hypoxia-Reoxygenationand High Glucose, Regulated by H2S in Primary Cardiomyocyte Cultures

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Abstract
Under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, myocardial oxidative stress increases, leading to cellular damage. Inhibition of oxidative stress has been reported to be involved in the cardioprotective effects of hydrogen sulfide (H2S) during I/R and diabetes. Recent studies have shown that H2S has the potential to protect the heart. However, the mechanism by which H2S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H2S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia/reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD signaling pathway and the PPAR-γ/PGC1α/AMPK/GLUT4 signaling pathway. Treatment with NaHS (100 μM) as an H2S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both experimental conditions increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH4) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2´-deoxyguanosine, and dihydrobiopterin (BH2) concentrations. Additionally, H2S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD and CAT, and decreased the expression of Keap1, p47phox y NOX4. Treatment with the H2S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and cardiomyocyte ultrastructure.

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