title: Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This phenotype is sustained by the activation of the Src/signal transducer and activator of transcription 3 (STAT3) axis, maintained by a positive feedback loop involving miR-204 and followed by an aberrant expression/activation of its downstream targets such as Pim1 and nuclear factor of activated T-cells (NFATc2). Dehydroepiandrosterone (DHEA) is a steroid hormone shown to reverse vascular remodeling in systemic vessels. Since STAT3 has been described as modulated by DHEA, we hypothesized that DHEA reverses human pulmonary hypertension by inhibiting Src/STAT3 constitutive activation. Using PASMCs isolated from patients with PAH (n = 3), we demonstrated that DHEA decreases both Src and STAT3 activation (Western blot and nuclear translocation assay), resulting in a significant reduction of Pim1, NFATc2 expression/activation (quantitative RT-PCR and Western blot), as well as Survivin and upregulation of bone morphogenetic protein receptor 2 (BMPR2) and miR-204. Src/STAT3 axis inhibition by DHEA is associated with 1) mitochondrial membrane potential (tetramethylrhodamine methyl-ester perchlorate; n = 150; P < 0.05) depolarization increasing apoptosis by 25% (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; n = 150; P < 0.05); and 2) decreased intracellular Ca(2+) concentration (fluo-3 AM; n = 150; P < 0.05) and proliferation by 30% (PCNA). Finally, in vivo similarly to STAT3 inhibition DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy. These effects were associated with the inhibition of Src, STAT3, Pim1, NFATc2, and Survivin and the upregulation of BMPR2 and miR-204. We demonstrated that DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3.
authors: Department of Medicine, Laval University, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Québec City, Quebec, Canada.
authors: Roxane
authors: R
authors: Paulin
authors: Jolyane
authors: J
authors: Meloche
authors: Maria Helena
authors: MH
authors: Jacob
authors: Malik
authors: M
authors: Bisserier
authors: Audrey
authors: A
authors: Courboulin
authors: Sébastien
authors: S
authors: Bonnet
mesh_terms: D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D035683:MicroRNAs / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D016686:Monocrotaline; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D050778:NFATC Transcription Factors / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D014665:Vasodilator Agents / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; C107489:BIRC5 protein, human; C516989:Birc5 protein, rat; D051034:Inhibitor of Apoptosis Proteins; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D000077022:Survivin; D014665:Vasodilator Agents; D003687:Dehydroepiandrosterone; D016686:Monocrotaline; D019061:src-Family Kinases; C496634:PIM1 protein, human; C496637:Pim1 protein, rat; D051573:Proto-Oncogene Proteins c-pim-1; C498218:BMPR2 protein, human; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II; D002118:Calcium