Enhancement of PPAR-beta activity by repetitive low-grade H(2)O(2) 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 microM) of H(2)O(2) in culture for 4 weeks. We then examined the effects of repetitive stress on PPAR-beta expression and activity as well as the role of PPAR-beta in the protective potency of repetitive stress. Our results show that repetitive stress enhances PPAR-beta expression and activity, thereby inhibiting oxidative stress-induced apoptosis. Further, PPAR-beta-directed antisense oligonucleotides reduced the PPAR-beta protein content, enhanced the H(2)O(2)-mediated apoptosis, and ablated the protective effect of repetitive low-grade H(2)O(2) stress. The specific PPAR-beta agonist L-165041 significantly potentiated the apoptosis induced by H(2)O(2) (p<0.05) and increased the protective effect of repetitive stress. These findings indicate that repetitive low-grade H(2)O(2) stress protects HUVECs from subsequent oxidative stress-induced apoptosis by enhancing PPAR-beta expression and activity.