Peroxisome Proliferator-Activated Receptor δ Regulates Extracellular Matrix and Apoptosis of Vascular Smooth Muscle Cells Through the Activation of Transforming Growth Factor-β1/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-beta 1 and its effector, Smad3. Activation of PPAR delta 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 PPAR delta on the expression of type III collagen was dually regulated by the direct binding of PPAR delta and Smad3 to a direct repeat-1 site and a Smad-binding element, respectively, in the type III collagen gene promoter. The activation of PPAR delta 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 PPAR delta ligand GW501516 to mice also suppressed elastase-induced cell death of aortic VSMCs. These results suggest that PPAR delta-induced upregulation of extracellular matrix proteins exerts an antiapoptotic effect, thereby maintaining the stability of atherosclerotic plaques. Specific ligands of PPAR delta may aid in the therapeutic intervention of atherosclerosis by improving plaque stability and patient prognosis. (Circ Res. 2009; 105: 16-24.)