Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways.
Pulmonary arterial hypertension (PAH) is a fatal condition for which there is no cure. Dimethyl Fumarate (DMF) is an FDA approved anti-oxidative and anti-inflammatory agent with a favorable safety record. The goal of this study was to assess the effectiveness of DMF as a therapy for PAH using patient-derived cells and murine models. We show that DMF treatment is effective in reversing hemodynamic changes, reducing inflammation, oxidative damage, and fibrosis in the experimental models of PAH and lung fibrosis. Our findings indicate that effects of DMF are facilitated by inhibiting pro-inflammatory NFκB, STAT3 and cJUN signaling, as well as βTRCP-dependent degradation of the pro-fibrogenic mediators Sp1, TAZ and β-catenin. These results provide a novel insight into the mechanism of its action. Collectively, preclinical results demonstrate beneficial effects of DMF on key molecular pathways contributing to PAH, and support its testing in PAH treatment in patients.
Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, MA, USA.
Agnieszka P
AP
Grzegorzewska
Boston University School of Medicine, Vascular Biology Section, Boston, MA, USA.
Francesca
F
Seta
Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, MA, USA.
Rong
R
Han
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, USA.
Caitlin A
CA
Czajka
Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, MA, USA.
Katsunari
K
Makino
Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, MA, USA.
Lukasz
L
Stawski
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, USA.|Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, USA.
Jeffrey S
JS
Isenberg
Boston University School of Medicine, Microbiology, Boston, MA, USA.
Jeffrey L
JL
Browning
Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, MA, USA.
Maria
M
Trojanowska
D000818:Animals; D015415:Biomarkers; D001761:Bleomycin / Q000009:adverse effects; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D015415:Biomarkers; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; D001761:Bleomycin; D046988:Proteasome Endopeptidase Complex; D000069462:Dimethyl Fumarate