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Antioxid Redox Signal. 2019 Feb 25. doi: 10.1089/ars.2018.7695. [Epub ahead of print]

Redox Biology of Peroxisome Proliferator-Activated Receptor-γ in Pulmonary Hypertension.

Author information

1
1 Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.
2
2 Atlanta Veterans Affairs Medical Center, Decatur, Georgia.

Abstract

SIGNIFICANCE:

Peroxisome proliferator-activated receptor-gamma (PPARγ) maintains pulmonary vascular health through coordination of antioxidant defense systems, inflammation, and cellular metabolism. Insufficient PPARγ contributes to pulmonary hypertension (PH) pathogenesis, whereas therapeutic restoration of PPARγ activity attenuates PH in preclinical models. Recent Advances: Numerous studies in the past decade have elucidated the complex mechanisms by which PPARγ in the pulmonary vasculature and right ventricle (RV) protects against PH. The scope of PPARγ-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, PPARγ 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 PPARγ 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 PPARγ pathways are critically disrupted across PH disease subtypes and lack of optimal pharmacological ligands.

FUTURE DIRECTIONS:

Recent studies indicate that ligand-induced posttranslational modifications of the PPARγ receptor differentially induce therapeutic benefits versus adverse side effects of PPARγ receptor activation. Strategies to selectively target PPARγ activity in diseased cells of pulmonary circulation and RV, coupled with development of ligands designed to specifically regulate posttranslational PPARγ modifications, may unlock the full therapeutic potential of this versatile master transcriptional and metabolic regulator in PH.

KEYWORDS:

PPARγ; antioxidants; hypoxia; oxidative stress; pulmonary hypertension; thiazolidinedione

PMID:
30582337
DOI:
10.1089/ars.2018.7695

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