Enhancement of PPAR-β activity by repetitive low-grade H2O2 stress protects human umbilical vein endothelial cells from subsequent oxidative stress-induced apoptosis

Repetitive stress has been shown to up-regulate antioxidant defense and increase survival after subsequent oxidative injury. The up-regulation of antioxidant defense has been identified as an underlying cause of the apoptosis-inhibitory effects exerted by repetitive stress. However, it remains unclear what the important signaling mechanisms are by which cells preexposed to low-grade stress deal with apoptosis-inducing stress. In this study, we repetitively stressed human umbilical vein endothelial cells (HUVECs) through multiple exposures to a low dose (30 μM) of H2O2 in culture for 4 weeks. We then examined the effects of repetitive stress on PPAR-β expression and activity as well as the role of PPAR-β in the protective potency of repetitive stress. Our results show that repetitive stress enhances PPAR-β expression and activity, thereby inhibiting oxidative stress-induced apoptosis. Further, PPAR-β-directed antisense oligonucleotides reduced the PPAR-β protein content, enhanced the H2O2-mediated apoptosis, and ablated the protective effect of repetitive low-grade H2O2 stress. The specific PPAR-β agonist L-165041 significantly potentiated the apoptosis induced by H2O2 (p < 0.05) and increased the protective effect of repetitive stress. These findings indicate that repetitive low-grade H2O2 stress protects HUVECs from subsequent oxidative stress-induced apoptosis by enhancing PPAR-β expression and activity.