FIG. 3.

Schematic view of PPARγ-dependent and -independent signaling pathways. PPARγ ligands can exert their effects in cardiovascular cells through PPARγ-dependent and -independent mechanisms. PPARγ-mediated increases in IRF-1 and GADD45 result in greater VSMC apoptosis. PPARγ-dependent decreases in c-fos expression attenuate VSMC proliferation. Ligand-activated PPARγ inhibits NF-κB transcriptional activity and inflammation in cardiovascular cells. PPARγ ligand–independent signaling can decrease IκB kinase activity, leading to decreased IκBα phosphorylation, NF-κB transcriptional activity, and inflammation. Another example of PPARγ ligand signaling that occurs independent of PPARγ involves nitroalkylation of the p65 subunit and eventual reduction in NF-κB activity and inflammation. Pioglitazone can regulate mitochondrial oxidative capacity and normalize lipid oxidation through direct binding to the mitoNEET protein, independent of PPARγ.