title: Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation.
  
  
  OBJECTIVE
  We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential.
  
  
  RESULTS
  Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1α activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1α activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1α activation by CoCl(2) or desferrioxamine causes DRP1-mediated fission. HIF-1α inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH.
  
  
  CONCLUSIONS
  DRP-1-mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.
authors.affiliation: Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.forename: Peter T
authors.initials: PT
authors.lastname: Toth
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.forename: Xichen
authors.initials: X
authors.lastname: Wu
authors.forename: Yong-Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: Thenappan
authors.initials: T
authors.lastname: Thenappan
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogoriler
authors.forename: Yimei
authors.initials: Y
authors.lastname: Chen
authors.forename: Erik
authors.initials: E
authors.lastname: Morrow
authors.forename: E Kenneth
authors.initials: EK
authors.lastname: Weir
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D016022:Case-Control Studies; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt; D056744:Cyclin B1 / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D065627:Familial Primary Pulmonary Hypertension; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D006019:Glycolysis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000628:therapy; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000201:enzymology / Q000473:pathology; D052999:Quinazolinones / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine; D013997:Time Factors; D014162:Transfection
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D000959:Antihypertensive Agents; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D003035:Cobalt; D012694:Serine; D016686:Monocrotaline; D016203:CDC2 Protein Kinase; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins; C018021:cobaltous chloride