Redox Biology of Peroxisome Proliferator-Activated Receptor-gamma in Pulmonary Hypertension

摘要

Recent Advances: Numerous studies in the past decade have elucidated the complex mechanisms by which PPAR gamma in the pulmonary vasculature and right ventricle (RV) protects against PH. The scope of PPAR gamma-interconnected pathways continues to expand and includes induction of antioxidant genes, transrepression of inflammatory signaling, regulation of mitochondrial biogenesis and bioenergetic integrity, control of cell cycle and proliferation, and regulation of vascular tone through interactions with nitric oxide and endogenous vasoactive molecules. Furthermore, PPAR gamma interacts with an extensive regulatory network of transcription factors and microRNAs leading to broad impact on cell signaling. Critical Issues: Abundant evidence suggests that targeting PPAR gamma exerts diverse salutary effects in PH and represents a novel and potentially translatable therapeutic strategy. However, progress has been slowed by an incomplete understanding of how specific PPAR gamma pathways are critically disrupted across PH disease subtypes and lack of optimal pharmacological ligands. Future Directions: Recent studies indicate that ligand-induced post-translational modifications of the PPAR gamma receptor differentially induce therapeutic benefits versus adverse side effects of PPAR gamma receptor activation. Strategies to selectively target PPAR gamma activity in diseased cells of pulmonary circulation and RV, coupled with development of ligands designed to specifically regulate post-translational PPAR gamma modifications, may unlock the full therapeutic potential of this versatile master transcriptional and metabolic regulator in PH.