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Background: PPAR␦ is a ligand-activated transcriptional factor that has been implicated in the vascular homeostasis. Results: Activation of PPAR␦ significantly attenuated Ang II-induced senescence of VSMCs by up-regulation of PTEN and ensuing modulation of the PI3K/Akt signaling. Conclusion: PPAR␦ inhibits Ang II-induced senescence of VSMCs via PTEN-mediated inhibition of ROS generation. Significance: PPAR␦ provides a novel insight into the treatment of atherosclerotic vascular disease.

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Although the peroxisome proliferator-activated receptor (PPAR) δ has been implicated in the wound healing process, its exact role and mechanism of action have not been fully elucidated. Our previous findings showed that PPARδ induces the expression of the transforming growth factor (TGF)-β1, which has been implicated in the deposit of extracellular matrix proteins. Here, we demonstrate that administration of GW501516, a specific PPARδ ligand, significantly promoted wound closure in the experimental mouse and had a profound effect on the expression of collagen types I and III, alpha-smooth muscle actin, pSmad3 and TGF-β1, which play a pivotal role in wound healing processes. Activation of PPARδ increased migration of human epidermal keratinocytes and dermal fibroblasts in in vitro scrape-wounding assays. Addition of a specific ALK5 receptor inhibitor SB431542 significantly suppressed GW501516-induced migration of human keratinocytes and fibroblasts. In these cells, activated PPARδ also induced the expression of collagen types I and III and fibronectin in a TGF-β1-dependent or -independent manner. The effect of PPARδ on the expression of type III collagen was dually regulated by the direct binding of PPARδ and Smad3 to a direct repeat-1 site and a Smad-binding element, respectively, of the type III gene promoter. Taken together, these results demonstrated that PPARδ plays an important role in skin wound healing in vivo and that it functions by accelerating extracellular matrix-mediated cellular interactions in a process mediated by the TGF-β1/Smad3 signaling-dependent or - independent pathway.

Yeast-based functional screening of a human glioblastoma cDNA library identified ras-related nuclear protein (Ran) as a novel suppressor of Bcl-2-associated X protein (Bax), a pro-apoptotic member of the Bcl-2 family of proteins. Yeast cells that expressed human Ran were resistant to Bax-induced cell death. In U373MG glioblastoma cells, stable overexpression of Ran significantly attenuated apoptotic cell death induced by the chemotherapeutic agent paclitaxel. FACS analysis demonstrated that Ran is involved in paclitaxel-induced cell cycle arrest. Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3. Paclitaxel-induced phosphorylation of c-JUN N-terminal kinase (JNK), but not p38, extracellular signal-regulated kinase and Akt, was markedly suppressed in U373MG cells that stably expressed Ran. These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways.