ArticleFree radical biology & medicine2013
Hypoxia downregulates PPARγ via an ERK1/2-NF-κB-Nox4-dependent mechanism in human pulmonary artery smooth muscle cells.
Article in Free radical biology & medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 68 citations in OpenAlex.
- NF-κB signaling as a critical inflammatory node in pulmonary arterial hypertension: from vascular remodeling to right heart failure.Frontiers in immunology · 2026Review
- Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025Review
- NADPH oxidases: redox regulation of cell homeostasis and disease.Physiological reviews · 2025Review
- Network pharmacology and experimental verification to investigate the mechanism of isoliquiritigenin for the treatment of Alzheimer's disease.Scientific reports · 2025Article
- The impact of high altitude (hypobaric hypoxia) on insulin resistance in humans.Journal of physiology and biochemistry · 2025Review
- An Evidence-Based Narrative Review of Scleral Hypoxia Theory in Myopia: From Mechanisms to Treatments.International journal of molecular sciences · 2025Review
- Role of environmental pollutants-induced ferroptosis in pulmonary diseases.Frontiers in medicine · 2025Review
- Hypoxia-Induced Insulin Resistance Mediates the Elevated Cardiovascular Risk in Patients with Obstructive Sleep Apnea: A Comprehensive Review.Reviews in cardiovascular medicine · 2024Review
- Pulmonary Hypertension and Hyperglycemia-Not a Sweet Combination.Diagnostics (Basel, Switzerland) · 2024Review
- Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure.International journal of molecular sciences · 2022Review
- Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance.Journal of physiology and biochemistry · 2021Article
- Therapeutic Opportunities for Intestinal Angioectasia- Targeting PPARγ and Oxidative Stress.Clinical and translational science · 2021Observational
- PPARγ increases HUWE1 to attenuate NF-κB/p65 and sickle cell disease with pulmonary hypertension.Blood advances · 2021Article
- NF-κB/p65 Competes With Peroxisome Proliferator-Activated Receptor Gamma for Transient Receptor Potential Channel 6 in Hypoxia-Induced Human Pulmonary Arterial Smooth Muscle Cells.Frontiers in cell and developmental biology · 2021Article
- Oxidative Stress, Kinase Activation, and Inflammatory Pathways Involved in Effects on Smooth Muscle Cells During Pulmonary Artery Hypertension Under Hypobaric Hypoxia Exposure.Frontiers in physiology · 2021Review
- Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension.Advances in experimental medicine and biology · 2021Review
- Cellular Pathways Promoting Pulmonary Vascular Remodeling by Hypoxia.Physiology (Bethesda, Md.) · 2020Review
- Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Novel Regulators and Targets of Redox Signaling in Pulmonary Vasculature.Current opinion in physiology · 2019Article
- Regulation of Smooth Muscle Cell Proliferation by NADPH Oxidases in Pulmonary Hypertension.Antioxidants (Basel, Switzerland) · 2019Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The ligand-activated transcription factor peroxisome proliferator-activated receptor γ (PPARγ) regulates metabolism, cell proliferation, and inflammation. Pulmonary hypertension (PH) is associated with reduced PPARγ expression, and hypoxia exposure regimens that cause PH reduce PPARγ expression. This study examines mechanisms of hypoxia-induced PPARγ downregulation in vitro and in vivo. Hypoxia reduced PPARγ mRNA and protein levels, PPARγ activity, and the expression of PPARγ-regulated genes in human pulmonary artery smooth muscle cells (HPASMCs) exposed to 1% oxygen for 72 h. Similarly, exposure of mice to hypoxia (10% O₂) for 3 weeks reduced PPARγ mRNA and protein in mouse lung. Inhibiting ERK1/2 with PD98059 or treatment with siRNA directed against either NF-κB p65 or Nox4 attenuated hypoxic reductions in PPARγ expression and activity. Furthermore, degradation of H₂O₂ using PEG-catalase prevented hypoxia-induced ERK1/2 phosphorylation and Nox4 expression, suggesting sustained ERK1/2-mediated signaling and Nox4 expression in this response. Mammalian two-hybrid assays demonstrated that PPARγ and p65 bind directly to each other in a mutually repressive fashion. We conclude from these results that hypoxic regimens that promote PH pathogenesis and HPASMC proliferation reduce PPARγ expression and activity through ERK1/2-, p65-, and Nox4-dependent pathways. These findings provide novel insights into mechanisms by which pathophysiological stimuli such as hypoxia cause loss of PPARγ activity and pulmonary vascular cell proliferation, pulmonary vascular remodeling, and PH. These results also indicate that restoration of PPARγ activity with pharmacological ligands may provide a novel therapeutic approach in selected forms of PH.
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Registered trials
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