Activation of peroxisome proliferator-activated receptor δ inhibits angiotensin II-induced activation of matrix metalloproteinase-2 in vascular smooth muscle cells.

We investigated the role of peroxisome proliferator-activated receptor (PPAR) δ on angiotensin (Ang) II-induced activation of matrix metalloproteinase (MMP)-2 in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, attenuated Ang II-induced activation of MMP-2 in a concentration-dependent manner. GW501516 also inhibited the generation of reactive oxygen species in VSMCs treated with Ang II. A marked increase in the mRNA levels of tissue inhibitor of metalloproteinase (TIMP)-2 and -3, endogenous antagonists of MMPs, was also observed in GW501516-treated VSMCs. These effects were markedly reduced in the presence of siRNAs against PPARδ, indicating that the effects of GW501516 are PPARδ dependent. Among the protein kinases inhibited by GW501516, suppression of phosphatidylinositol 3-kinase/Akt signaling was shown to have the greatest effect on activation of MMP-2 in VSMCs treated with Ang II. Concomitantly, GW501516-mediated inhibition of MMP-2 activation in VSMCs treated with Ang II was associated with the suppression of cell migration to levels approaching those in cells not exposed to Ang II. Thus, activation of PPARδ confers resistance to Ang II-induced degradation of the extracellular matrix by upregulating expression of its endogenous inhibitor TIMP and thereby modulating cellular responses to Ang II in vascular cells.

Ham SA ，Lee H ，Hwang JS ，Kang ES ，Yoo T ，Paek KS ，Do JT ，Park C ，Oh JW ，Kim JH ，Han CW ，Seo HG ... -  《-》

Activation of PPARδ counteracts angiotensin II-induced ROS generation by inhibiting rac1 translocation in vascular smooth muscle cells.

Lee H ，Ham SA ，Kim MY ，Kim JH ，Paek KS ，Kang ES ，Kim HJ ，Hwang JS ，Yoo T ，Park C ，Kim JH ，Lim DS ，Han CW ，Seo HG ... -  《-》

Ligand-activated PPARδ inhibits angiotensin II-stimulated hypertrophy of vascular smooth muscle cells by targeting ROS.

Kang ES ，Hwang JS ，Lee WJ ，Lee GH ，Choi MJ ，Paek KS ，Lim DS ，Seo HG ... -  《PLoS One》

PPARδ coordinates angiotensin II-induced senescence in vascular smooth muscle cells through PTEN-mediated inhibition of superoxide generation.

Kim HJ ，Ham SA ，Kim MY ，Hwang JS ，Lee H ，Kang ES ，Yoo T ，Woo IS ，Yabe-Nishimura C ，Paek KS ，Kim JH ，Seo HG ... -  《-》

Ligand-Activated Peroxisome Proliferator-Activated Receptor δ Attenuates Vascular Oxidative Stress by Inhibiting Thrombospondin-1 Expression.

Thrombospondin-1 (TSP-1) is implicated in vascular diseases associated with oxidative stress, such as abdominal aortic aneurysms, ischemia-reperfusion injury, and atherosclerosis. However, the regulatory mechanisms underlying TSP-1 expression are not fully elucidated. In this study, we found that peroxisome proliferator-activated receptor δ (PPARδ) inhibited oxidative stress-induced TSP-1 expression and migration in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly attenuated hydrogen peroxide (H2O2)-induced expression of TSP-1 in VSMCs. Small interfering RNA-mediated knockdown of PPARδ and treatment with GSK0660, a selective PPARδ antagonist, reversed the effect of GW501516 on H2O2-induced expression of TSP-1, suggesting that PPARδ is associated with GW501516 activity. Furthermore, JNK (c-Jun N-terminal kinase), but not p38 and ERK (extracellular signal-regulated kinase), mediated PPARδ-dependent inhibition of TSP-1 expression in VSMCs exposed to H2O2. GW501516- activated PPARδ also reduced the H2O2-induced generation of reactive oxygen species, concomitant with inhibition of VSMC migration. In particular, TSP-1 contributed to the action of PPARδ in the regulation of H2O2-induced interleukin-1β expression. These results suggest that PPARδ-modulated downregulation of TSP-1 is associated with reduced cellular oxidative stress, thereby inhibiting H2O2-induced pheno-typic changes in vascular cells.

Ahn MY ，Ham SA ，Yoo T ，Lee WJ ，Hwang JS ，Paek KS ，Lim DS ，Han SG ，Lee CH ，Seo HG ... -  《-》