PPARgamma as a potential therapeutic target in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a progressive disorder of the pulmonary circulation associated with significant morbidity and mortality. The pathobiology of PH involves a complex series of derangements causing endothelial dysfunction, vasoconstriction and abnormal proliferation of pulmonary vascular wall cells that lead to increases in pulmonary vascular resistance and pressure. Recent evidence indicates that the ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma) can have a favorable impact on a variety of pathways involved in the pathogenesis of PH. This review summarizes PPARgamma biology and the emerging evidence that therapies designed to activate this receptor may provide novel approaches to the treatment of PH. Mediators of PH that are regulated by PPARgamma are reviewed to provide insights into potential mechanisms underlying therapeutic effects of PPARgamma ligands in PH.

Figure 1

Putative pathways by which PPARγ participates in pulmonary hypertension pathogenesis and therapy. As illustrated in the left panel, under normal circumstances, current evidence indicates that PPARγ stimulates (→) or inhibits (⊣) several pathways involved in pulmonary hypertension pathogenesis including inhibition of NADPH oxidase and stimulation of endothelial nitric oxide (NO), effects that collectively enhance NO bioavailability. PPARγ can also inhibit endothelin-1 (ET-1) and platelet-derived growth factor (PDGF) signaling, stimulate phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, inhibit inflammation and Cox-2 expression as well as thromboxane (Tx) production, and stimulate endothelial progenitor cell (EPC) activity. As shown in the middle panel, reduced PPARγ expression (red text) can promote pulmonary hypertension through abnormal proliferation of endothelial and smooth muscle cells resulting in intimal and medial proliferation and thickening that reduces the vascular lumen and increases pulmonary vascular resistance. The mechanisms for abnormal pulmonary vascular cell proliferation may relate to the effects of impaired PPARγ signaling (dashed lines). As depicted in the right panel, PPARγ ligands (green) and activation of the PPARγ receptor can normalize PPARγ signaling to attenuate or reverse endothelial dysfunction, abnormal cell proliferation, and pulmonary vascular remodeling.