Peroxisome proliferator-activated receptor {delta} regulates extracellular matrix and apoptosis of vascular smooth muscle cells through the activation of transforming growth factor-{beta}1/Smad3.
Homeostasis of the extracellular matrix and apoptosis of vascular smooth muscle cells (VSMCs) are key components in the regulation of the stability of atherosclerotic plaques. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR)delta regulates extracellular matrix synthesis and degradation through transforming growth factor-beta1 and its effector, Smad3. Activation of PPARdelta strongly amplified the expression of types I and III collagen, fibronectin, elastin, and TIMP-3 (tissue inhibitor of metalloproteinases 3), but not of TIMP-1, matrix metalloproteinase-2 or -9. The effect of PPARdelta on the expression of type III collagen was dually regulated by the direct binding of PPARdelta and Smad3 to a direct repeat-1 site and a Smad-binding element, respectively, in the type III collagen gene promoter. The activation of PPARdelta attenuated apoptotic cell death in VSMCs induced by oxidized low-density lipoprotein, and similar antiapoptotic effects were observed on treatment of cells with exogenous type I and/or III collagen. Administration of a PPARdelta ligand GW501516 to mice also suppressed elastase-induced cell death of aortic VSMCs. These results suggest that PPARdelta-induced upregulation of extracellular matrix proteins exerts an antiapoptotic effect, thereby maintaining the stability of atherosclerotic plaques. Specific ligands of PPARdelta may aid in the therapeutic intervention of atherosclerosis by improving plaque stability and patient prognosis.
Kim
Hyo Jung
HJ
Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Chilam-Dong, Jinju, Korea.
Kim
Min Young
MY
Jin
Hana
H
Kim
Hyun Joon
HJ
Kang
Sang Soo
SS
Kim
Hye Jung
HJ
Lee
Jae Heun
JH
Chang
Ki Churl
KC
Hwang
Jin-Yong
JY
Yabe-Nishimura
Chihiro
C
Kim
Jin-Hoi
JH
Seo
Han Geuk
HG
D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006706:Homeostasis; D006801:Humans; D008024:Ligands; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D008024:Ligands; D047494:PPAR delta; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1