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Article: Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis

Kato, Kosuke / Papageorgiou, Ioannis / Shin, Yoon-Joo / Kleinhenz, Jennifer M. / Palumbo, Sunny / Hahn, Seongmin / Irish, Joseph D. / Rounseville, Skye P. / Knox, Kenneth S. / Hecker, Louise

Antioxidants. 2022 Feb. 28, v. 11, no. 3

2022

Abstract: Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3–6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.
Keywords	active pharmaceutical ingredients ; animal models ; antioxidants ; dimethyl fumarate ; drugs ; fibroblasts ; fibrosis ; lungs ; oxidative stress ; pulmonary fibrosis ; sclerosis
Language	English
Dates of publication	2022-0228
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11030492
Database	NAL-Catalogue (AGRICOLA)

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Article: Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.

Kato, Kosuke / Papageorgiou, Ioannis / Shin, Yoon-Joo / Kleinhenz, Jennifer M / Palumbo, Sunny / Hahn, Seongmin / Irish, Joseph D / Rounseville, Skye P / Knox, Kenneth S / Hecker, Louise

Antioxidants (Basel, Switzerland)

2022 Volume 11, Issue 3

Abstract	Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3-6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.
Language	English
Publishing date	2022-02-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11030492
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Article ; Online: Time-dependent PPARγ Modulation of HIF-1α Signaling in Hypoxic Pulmonary Artery Smooth Muscle Cells.

Blum, Justine I / Bijli, Kaiser M / Murphy, Tamara C / Kleinhenz, Jennifer M / Hart, C Michael

The American journal of the medical sciences

2016 Volume 352, Issue 1, Page(s) 71–79

Abstract: Background: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the ... ...

Abstract	Background: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation. In the current study, we determined whether PPARγ inhibits HIF-1α and PDK-1 expression in human PASMCs. Methods: HPASMCs were exposed to normoxia (21% O2) or hypoxia (1% O2) for 2-72 hours ± treatment with the PPARγ-ligand, rosiglitazone (RSG, 10μM). Results: Compared to normoxia, HIF-1α mRNA levels were elevated in HPASMC at 2 hours hypoxia and reduced to baseline levels by 24-72 hours. HIF-1α protein levels increased following 4 and 8 hours of hypoxia and returned to baseline levels by 24 and 72 hours. PDK-1 protein levels increased following 24 hours hypoxia and remained elevated by 72 hours. RSG treatment at the onset of hypoxia attenuated HIF-1α protein and PDK-1 mRNA and protein levels at 4, 8 and 24 hours of hypoxia, respectively. However, RSG treatment during final 24 hours of 72-hour hypoxia, an intervention that inhibits HPASMC proliferation, failed to prevent hypoxia-induced PDK-1 expression. Conclusion: Hypoxia causes transient activation of HPASMC HIF-1α that is attenuated by RSG treatment initiated at hypoxia onset. These findings provide novel evidence that PPARγ modulates fundamental and acute cellular responses to hypoxia through both HIF-1-dependent and HIF-1-independent mechanisms.
MeSH term(s)	Cell Proliferation/drug effects ; Humans ; Hypoxia/physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Ligands ; Myocytes, Smooth Muscle/physiology ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Pulmonary Artery/physiopathology ; Signal Transduction ; Thiazolidinediones/pharmacology
Chemical Substances	HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Ligands ; PPAR gamma ; Thiazolidinediones ; rosiglitazone (05V02F2KDG) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; pyruvate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.2)
Language	English
Publishing date	2016-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	82078-7
ISSN	1538-2990 ; 0002-9629
ISSN (online)	1538-2990
ISSN	0002-9629
DOI	10.1016/j.amjms.2016.03.019
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Article ; Online: SARS-CoV-2 Evolution and Immune Escape in Immunocompromised Patients.

The New England journal of medicine

2022 Volume 386, Issue 25, Page(s) 2436–2438

MeSH term(s)	Antibodies, Viral ; Antigenic Drift and Shift ; COVID-19 ; Evolution, Molecular ; Humans ; Immunocompromised Host ; Neutralization Tests ; SARS-CoV-2
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2022-06-08
Publishing country	United States
Document type	Letter
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc2202861
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Article ; Online: Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung.

Kang, Bum-Yong / Park, Kathy / Kleinhenz, Jennifer M / Murphy, Tamara C / Sutliff, Roy L / Archer, David / Hart, C Michael

American journal of respiratory cell and molecular biology

2017 Volume 56, Issue 1, Page(s) 131–144

Abstract: Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis ...

Abstract	Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis of SCD-PH remains incompletely defined. This study examines peroxisome proliferator-activated receptor γ (PPARγ) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPARγ agonist, rosiglitazone (RSG), 10 mg/kg/day, or vehicle for 10 days. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle or hemin for 72 hours, and selected HPAECs were treated with RSG. SS mice developed PH and right ventricular hypertrophy associated with reduced lung levels of PPARγ and increased levels of microRNA-27a (miR-27a), v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), endothelin-1 (ET-1), and markers of endothelial dysfunction (platelet/endothelial cell adhesion molecule 1 and E selectin). HPAECs treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPARγ levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPARγ overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPARγ with RSG attenuated reductions in PPARγ and increases in miR-27a, ET-1, and markers of endothelial dysfunction. In SCD-PH pathogenesis, ETS1 stimulates increases in miR-27a levels that reduce PPARγ and increase ET-1 and endothelial dysfunction. PPARγ activation attenuated SCD-associated signaling derangements, suggesting a novel therapeutic approach to attenuate SCD-PH pathogenesis.
MeSH term(s)	Anemia, Sickle Cell/metabolism ; Anemia, Sickle Cell/pathology ; Animals ; Blood Pressure/drug effects ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelin-1/metabolism ; Gene Knockdown Techniques ; Hemin/pharmacology ; Humans ; Hypertension, Pulmonary/complications ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/physiopathology ; Hypertrophy, Right Ventricular/complications ; Hypertrophy, Right Ventricular/genetics ; Hypertrophy, Right Ventricular/physiopathology ; Ligands ; Lung/pathology ; Mice ; MicroRNAs/metabolism ; Models, Biological ; PPAR gamma/metabolism ; Proto-Oncogene Protein c-ets-1/metabolism ; Pulmonary Artery/pathology ; Systole/drug effects ; Thiazolidinediones/pharmacology ; Up-Regulation/drug effects
Chemical Substances	ETS1 protein, human ; Endothelin-1 ; Ets1 protein, mouse ; Ligands ; MIRN27 microRNA, human ; MicroRNAs ; Mirn27 microRNA, mouse ; PPAR gamma ; Proto-Oncogene Protein c-ets-1 ; Thiazolidinediones ; rosiglitazone (05V02F2KDG) ; Hemin (743LRP9S7N)
Language	English
Publishing date	2017-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2016-0166OC
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Article ; Online: The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo.

Kang, Bum-Yong / Kleinhenz, Jennifer M / Murphy, Tamara C / Hart, C Michael

American journal of physiology. Lung cellular and molecular physiology

2011 Volume 301, Issue 6, Page(s) L881–91

Abstract: Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these ... ...

Abstract	Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these therapeutic effects. To test this hypothesis, human pulmonary artery endothelial cells (HPAECs) were exposed to normoxia or hypoxia (1% O(2)) for 72 h and treated with or without the PPARγ ligand rosiglitazone (RSG, 10 μM) during the final 24 h of exposure. HPAEC proliferation was measured with MTT assays or cell counting, and mRNA and protein levels of ET-1 signaling components were determined. To explore the role of hypoxia-activated transcription factors, selected HPAECs were treated with inhibitors of hypoxia-inducible factor (HIF)-1α (chetomin) or nuclear factor (NF)-κB (caffeic acid phenethyl ester, CAPE). In parallel studies, male C57BL/6 mice were exposed to normoxia (21% O(2)) or hypoxia (10% O(2)) for 3 wk with or without gavage with RSG (10 mg·kg(-1)·day(-1)) for the final 10 days of exposure. Hypoxia increased ET-1, endothelin-converting enzyme-1, and endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated hypoxia-induced activation of HIF-1α, NF-κB activation, and ET-1 signaling pathway components. Similarly, treatment with chetomin or CAPE prevented hypoxia-induced increases in HPAEC ET-1 mRNA and protein levels. These findings indicate that PPARγ activation attenuates a program of hypoxia-induced ET-1 signaling by inhibiting activation of hypoxia-responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit enhanced ET-1 signaling in PH pathogenesis.
MeSH term(s)	Animals ; Aspartic Acid Endopeptidases/genetics ; Aspartic Acid Endopeptidases/metabolism ; Cell Hypoxia ; Cell Proliferation/drug effects ; Endothelial Cells/metabolism ; Endothelin-1/genetics ; Endothelin-1/metabolism ; Endothelin-Converting Enzymes ; Gene Expression ; Gene Expression Regulation/drug effects ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lung/metabolism ; Lung/pathology ; Male ; Metalloendopeptidases/genetics ; Metalloendopeptidases/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/genetics ; NF-kappa B/metabolism ; PPAR gamma/agonists ; Pulmonary Artery/pathology ; Receptor, Endothelin A/genetics ; Receptor, Endothelin A/metabolism ; Receptor, Endothelin B/genetics ; Receptor, Endothelin B/metabolism ; Rosiglitazone ; Signal Transduction ; Thiazolidinediones/pharmacology
Chemical Substances	Endothelin-1 ; Hif1a protein, mouse ; Hypoxia-Inducible Factor 1, alpha Subunit ; NF-kappa B ; PPAR gamma ; Receptor, Endothelin A ; Receptor, Endothelin B ; Thiazolidinediones ; Rosiglitazone (05V02F2KDG) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Metalloendopeptidases (EC 3.4.24.-) ; ECE1 protein, human (EC 3.4.24.71) ; Ece1 protein, mouse (EC 3.4.24.71) ; Endothelin-Converting Enzymes (EC 3.4.24.71)
Language	English
Publishing date	2011-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00195.2011
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Article ; Online: SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies

medRxiv

Abstract: Background: SARSCoV2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood. Methods: We characterized ... ...

Abstract	Background: SARSCoV2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood. Methods: We characterized endogenous immune responses, within host SARSCoV2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies. Results: In two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARSCoV2. Conclusions: Our results underscore the potential importance of multiple factors the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics.
Keywords	covid19
Language	English
Publishing date	2022-04-19
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2022.04.12.22273675
Database	COVID19

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Article ; Online: PPARγ Regulates Mitochondrial Structure and Function and Human Pulmonary Artery Smooth Muscle Cell Proliferation.

Yeligar, Samantha M / Kang, Bum-Yong / Bijli, Kaiser M / Kleinhenz, Jennifer M / Murphy, Tamara C / Torres, Gloria / San Martin, Alejandra / Sutliff, Roy L / Hart, C Michael

American journal of respiratory cell and molecular biology

2017 Volume 58, Issue 5, Page(s) 648–657

Abstract: Pulmonary hypertension (PH) is a progressive disorder that causes significant morbidity and mortality despite existing therapies. PH pathogenesis is characterized by metabolic derangements that increase pulmonary artery smooth muscle cell (PASMC) ... ...

Abstract	Pulmonary hypertension (PH) is a progressive disorder that causes significant morbidity and mortality despite existing therapies. PH pathogenesis is characterized by metabolic derangements that increase pulmonary artery smooth muscle cell (PASMC) proliferation and vascular remodeling. PH-associated decreases in peroxisome proliferator-activated receptor γ (PPARγ) stimulate PASMC proliferation, and PPARγ in coordination with PPARγ coactivator 1α (PGC1α) regulates mitochondrial gene expression and biogenesis. To further examine the impact of decreases in PPARγ expression on human PASMC (HPASMC) mitochondrial function, we hypothesized that depletion of either PPARγ or PGC1α perturbs mitochondrial structure and function to stimulate PASMC proliferation. To test this hypothesis, HPASMCs were exposed to hypoxia and treated pharmacologically with the PPARγ antagonist GW9662 or with siRNA against PPARγ or PGC1α for 72 hours. HPASMC proliferation (cell counting), target mRNA levels (qRT-PCR), target protein levels (Western blotting), mitochondria-derived H
MeSH term(s)	Anilides/pharmacology ; Animals ; Cell Hypoxia ; Cell Proliferation ; Cells, Cultured ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/pathology ; Hypertension, Pulmonary/prevention & control ; Mice, Inbred C57BL ; Mitochondria, Muscle/drug effects ; Mitochondria, Muscle/metabolism ; Mitochondria, Muscle/pathology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; PPAR gamma/antagonists & inhibitors ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; RNA Interference
Chemical Substances	2-chloro-5-nitrobenzanilide ; Anilides ; PPAR gamma ; PPARG protein, human ; PPARGC1A protein, human ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ppargc1a protein, mouse
Language	English
Publishing date	2017-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2016-0293OC
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Article ; Online: Peroxisome proliferator-activated receptor gamma depletion stimulates Nox4 expression and human pulmonary artery smooth muscle cell proliferation.

Bijli, Kaiser M / Kleinhenz, Jennifer M / Murphy, Tamara C / Kang, Bum-Yong / Adesina, Sherry E / Sutliff, Roy L / Hart, C Michael

Free radical biology & medicine

2014 Volume 80, Page(s) 111–120

Abstract: Hypoxia stimulates pulmonary hypertension (PH) in part by increasing the proliferation of pulmonary vascular wall cells. Recent evidence suggests that signaling events involved in hypoxia-induced cell proliferation include sustained nuclear factor-kappaB ...

Abstract	Hypoxia stimulates pulmonary hypertension (PH) in part by increasing the proliferation of pulmonary vascular wall cells. Recent evidence suggests that signaling events involved in hypoxia-induced cell proliferation include sustained nuclear factor-kappaB (NF-κB) activation, increased NADPH oxidase 4 (Nox4) expression, and downregulation of peroxisome proliferator-activated receptor gamma (PPARγ) levels. To further understand the role of reduced PPARγ levels associated with PH pathobiology, siRNA was employed to reduce PPARγ levels in human pulmonary artery smooth muscle cells (HPASMC) in vitro under normoxic conditions. PPARγ protein levels were reduced to levels comparable to those observed under hypoxic conditions. Depletion of PPARγ for 24-72 h activated mitogen-activated protein kinase, ERK 1/2, and NF-κB. Inhibition of ERK 1/2 prevented NF-κB activation caused by PPARγ depletion, indicating that ERK 1/2 lies upstream of NF-κB activation. Depletion of PPARγ for 72 h increased NF-κB-dependent Nox4 expression and H2O2 production. Inhibition of NF-κB or Nox4 attenuated PPARγ depletion-induced HPASMC proliferation. Degradation of PPARγ depletion-induced H2O2 by PEG-catalase prevented HPASMC proliferation and also ERK 1/2 and NF-κB activation and Nox4 expression, indicating that H2O2 participates in feed-forward activation of the above signaling events. Contrary to the effects of PPARγ depletion, HPASMC PPARγ overexpression reduced ERK 1/2 and NF-κB activation, Nox4 expression, and cell proliferation. Taken together these findings provide novel evidence that PPARγ plays a central role in the regulation of the ERK1/2-NF-κB-Nox4-H2O2 signaling axis in HPASMC. These results indicate that reductions in PPARγ caused by pathophysiological stimuli such as prolonged hypoxia exposure are sufficient to promote the proliferation of pulmonary vascular smooth muscle cells observed in PH pathobiology.
MeSH term(s)	Antibodies, Neutralizing/pharmacology ; Catalase/pharmacology ; Cell Hypoxia ; Cell Proliferation/drug effects ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; Flavonoids/pharmacology ; Gene Expression Regulation ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/genetics ; Mitogen-Activated Protein Kinase 3/metabolism ; Models, Biological ; NADPH Oxidase 4 ; NADPH Oxidases/genetics ; NADPH Oxidases/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; PPAR gamma/antagonists & inhibitors ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Polyethylene Glycols/pharmacology ; Protein Kinase Inhibitors/pharmacology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Signal Transduction
Chemical Substances	Antibodies, Neutralizing ; Flavonoids ; NF-kappa B ; PPAR gamma ; Protein Kinase Inhibitors ; RNA, Small Interfering ; catalase-polyethylene glycol ; Polyethylene Glycols (30IQX730WE) ; Hydrogen Peroxide (BBX060AN9V) ; Catalase (EC 1.11.1.6) ; NADPH Oxidase 4 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-) ; NOX4 protein, human (EC 1.6.3.-) ; MAPK1 protein, human (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I)
Language	English
Publishing date	2014-12-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2014.12.019
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Article ; Online: Peroxisome Proliferator-Activated Receptor γ and microRNA 98 in Hypoxia-Induced Endothelin-1 Signaling.

Kang, Bum-Yong / Park, Kathy K / Kleinhenz, Jennifer M / Murphy, Tamara C / Green, David E / Bijli, Kaiser M / Yeligar, Samantha M / Carthan, Kristal A / Searles, Charles D / Sutliff, Roy L / Hart, C Michael

American journal of respiratory cell and molecular biology

2016 Volume 54, Issue 1, Page(s) 136–146

Abstract: Endothelin-1 (ET-1) plays a critical role in endothelial dysfunction and contributes to the pathogenesis of pulmonary hypertension (PH). We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) stimulates microRNAs that inhibit ET-1 and ... ...

Abstract	Endothelin-1 (ET-1) plays a critical role in endothelial dysfunction and contributes to the pathogenesis of pulmonary hypertension (PH). We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) stimulates microRNAs that inhibit ET-1 and pulmonary artery endothelial cell (PAEC) proliferation. The objective of this study was to clarify molecular mechanisms by which PPARγ regulates ET-1 expression in vitro and in vivo. In PAECs isolated from patients with pulmonary arterial hypertension, microRNA (miR)-98 expression was reduced, and ET-1 protein levels and proliferation were increased. Similarly, hypoxia reduced miR-98 and increased ET-1 levels and PAEC proliferation in vitro. In vivo, hypoxia reduced miR-98 expression and increased ET-1 and proliferating cell nuclear antigen (PCNA) levels in mouse lung, derangements that were aggravated by treatment with the vascular endothelial growth factor receptor antagonist Sugen5416. Reporter assays confirmed that miR-98 binds directly to the ET-1 3'-untranslated region. Compared with littermate control mice, miR-98 levels were reduced and ET-1 and PCNA expression were increased in lungs from endothelial-targeted PPARγ knockout mice, whereas miR-98 levels were increased and ET-1 and PCNA expression was reduced in lungs from endothelial-targeted PPARγ-overexpression mice. Gain or loss of PPARγ function in PAECs in vitro confirmed that alterations in PPARγ were sufficient to regulate miR-98, ET-1, and PCNA expression. Finally, PPARγ activation with rosiglitazone regimens that attenuated hypoxia-induced PH in vivo and human PAEC proliferation in vitro restored miR-98 levels. The results of this study show that PPARγ regulates miR-98 to modulate ET-1 expression and PAEC proliferation. These results further clarify molecular mechanisms by which PPARγ participates in PH pathogenesis and therapy.
MeSH term(s)	3' Untranslated Regions ; Animals ; Binding Sites ; Cell Proliferation ; Cells, Cultured ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Endothelin-1/genetics ; Endothelin-1/metabolism ; Gene Expression Regulation ; Humans ; Hypertension, Pulmonary/chemically induced ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/pathology ; Hypoxia/complications ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia/pathology ; Indoles ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/genetics ; MicroRNAs/metabolism ; PPAR gamma/agonists ; PPAR gamma/deficiency ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Pyrroles ; RNA Interference ; Signal Transduction/drug effects ; Thiazolidinediones/pharmacology ; Transfection ; Vascular Remodeling
Chemical Substances	3' Untranslated Regions ; Endothelin-1 ; Indoles ; MIRN98 microRNA, human ; MIRN98 microRNA, mouse ; MicroRNAs ; PPAR gamma ; Pyrroles ; Thiazolidinediones ; rosiglitazone (05V02F2KDG) ; Semaxinib (71IA9S35AJ)
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2014-0337OC
Database	MEDical Literature Analysis and Retrieval System OnLINE

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