title: Activation of peroxisome proliferator-activated receptor δ inhibits angiotensin II-induced activation of matrix metalloproteinase-2 in vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Animal Biotechnology, Animal Resources Research Center, Konkuk University, Seoul, Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Taesik
authors.initials: T
authors.lastname: Yoo
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.forename: Jeong Tae
authors.initials: JT
authors.lastname: Do
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Oh
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Han
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles
chemical_list: C425931:GW 501516; D047494:PPAR delta; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2