title: PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown.
  
  
  OBJECTIVE
  We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH.
  
  
  METHODS
  Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo.
  
  
  RESULTS
  In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 ± 35 vs. 245 ± 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 ± 0.02 vs. 0.38 ± 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 ± 0.8 vs. 19 ± 1.7%; P < 0.05). Lung vascularity was increased by MFN2.
  
  
  CONCLUSIONS
  Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.
authors: Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors: John J
authors: JJ
authors: Ryan
authors: Glenn
authors: G
authors: Marsboom
authors: Yong-Hu
authors: YH
authors: Fang
authors: Peter T
authors: PT
authors: Toth
authors: Erik
authors: E
authors: Morrow
authors: Nancy
authors: N
authors: Luo
authors: Lin
authors: L
authors: Piao
authors: Zhigang
authors: Z
authors: Hong
authors: Kyle
authors: K
authors: Ericson
authors: Hannah J
authors: HJ
authors: Zhang
authors: Mei
authors: M
authors: Han
authors: Chad R
authors: CR
authors: Haney
authors: Chin-Tu
authors: CT
authors: Chen
authors: Willard W
authors: WW
authors: Sharp
authors: Stephen L
authors: SL
authors: Archer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D017079:Exercise Tolerance / Q000187:drug effects; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D020558:GTP Phosphohydrolases / Q000172:deficiency*; D006360:Heat-Shock Proteins / Q000172:deficiency*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000166:cytology / Q000473:pathology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000172:deficiency; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000008:administration & dosage / Q000172:deficiency*; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000172:deficiency*
chemical_list: D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C489710:Mfn2 protein, rat