title: Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH.
abstract: Like cancer, pulmonary arterial hypertension (PAH) is characterised by a pro-proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension. Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K(+) current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca(2+) concentration ([Ca(2+)](i)), rho-associated coiled-coil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and suden/chronic hypoxia-induced PAH in rats. This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH.
authors.affiliation: Dept of Medicine, School of Medicine, Laval University, Quebec, Canada
authors.forename: Audrey
authors.initials: A
authors.lastname: Courboulin
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barrier
authors.forename: Tanya
authors.initials: T
authors.lastname: Perreault
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Veronique L
authors.initials: VL
authors.lastname: Tremblay
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Eve
authors.initials: E
authors.lastname: Tremblay
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambert
authors.forename: Maria H
authors.initials: MH
authors.lastname: Jacob
authors.forename: Sandra N
authors.initials: SN
authors.lastname: Bonnet
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000096:biosynthesis; D009285:Naphthoquinones / Q000627:therapeutic use*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D050778:NFATC Transcription Factors; D009285:Naphthoquinones; D024642:Potassium Channels, Voltage-Gated; D018809:Proliferating Cell Nuclear Antigen; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II; D002118:Calcium; C014758:plumbagin