Recent randomized controlled trials, including IRIS (Insulin Resistance Intervention After Stroke Trial), emphasize the beneficial effects of PPARγ agonists in PAH patients, leading to recent revival for clinical use.
However, early diabetes study results, their subsequent misinterpretations, errors in multiple published review articles, and rumors on potential adverse effects in the literature have dampened enthusiasm to consider pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH.
In conclusion, the activity of Cat S in pulmonary vascular remodeling and degradation of elastin fibers through the disruption of PPARγ is pathophysiologically significant in PAH.
We hypothesized that LRP1 (low-density lipoprotein receptor-related protein 1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGFβ1 signals and that the PPARγ agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (SMCs).
In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARγ agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure.
We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM.
Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.
Immunoblotting evealed IP, EP<sub>4</sub>, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue.
Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH).
We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH.
In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease).
Furthermore, the chapter also provides an overview on the cellular and molecular mechanisms involved in PPARgamma-mediated inhibitory effect on pulmonary vascular remodeling, a major contributor to the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension.
Because our recent clinical observations indicate that insulin resistance may be an environmental risk factor or disease modifier ("second hit"), we suggest that PPARgamma-activating agents might be beneficial in the future treatment of both insulin-resistant and insulin-sensitive PAH patients with or without BMP-RII mutations.