Peroxisome proliferator activated receptor γ Final Common Pathway

In the endothelium, PPARγ induces transcription of RBP7 and PPARγ/RBP7 together form a transcriptional regulatory hub promoting the expression of antioxidant genes, including adiponectin (AdipoQ), all of which promote an antioxidant environment, NO production, and NO bioavailability to the smooth muscle. In the vascular smooth muscle, endothelium-derived NO activates soluble guanylate cyclase to produce cGMP. To regulate cGMP levels in the cell, PPARγ induces the expression of Rho related BTB domain containing 1 (RhoBTB1), which acts as a substrate recognition protein delivering phosphodiesterase 5 (PDE5) to the Cullin-3 (CUL3) complex for ubiquitination and proteasomal degradation. The ensuing decrease in PDE5 activity promotes cGMP production and NO activity leading to vasodilation. Rho related BTB domain containing 1 also promotes a state of vessel distensibility reducing arterial stiffness. Other PPARγ target genes (RGS5 and TIMP4) control G protein receptor action, control myogenic tone, and reduce remodeling. Peroxisome proliferator activated receptor γ also acts as an antiinflammatory by shuttling p65 from the nucleus repressing expression of inflammatory genes.