title: Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung.
abstract: Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.
authors: Ohio State University, Columbus, OH 43210, USA.
authors: Yazhini
authors: Y
authors: Ravi
authors: Karuppaiyah
authors: K
authors: Selvendiran
authors: Shan K
authors: SK
authors: Naidu
authors: Sarath
authors: S
authors: Meduru
authors: Lucas A
authors: LA
authors: Citro
authors: Balázs
authors: B
authors: Bognár
authors: Mahmood
authors: M
authors: Khan
authors: Tamás
authors: T
authors: Kálai
authors: Kálmán
authors: K
authors: Hideg
authors: Periannan
authors: P
authors: Kuppusamy
authors: Chittoor B
authors: CB
authors: Sai-Sudhakar
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D006333:Heart Failure / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D030421:Peroxynitrous Acid / Q000032:analysis / Q000378:metabolism*; D010881:Piperidones / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography
chemical_list: C541427:(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one); D010881:Piperidones; D030421:Peroxynitrous Acid; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487216:Pten protein, rat