Document Detail


Pulmonary hypertension secondary to left-heart failure involves peroxynitrite-induced downregulation of PTEN in the lung.
MedLine Citation:
PMID:  23339168     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Yazhini Ravi; Karuppaiyah Selvendiran; Shan K Naidu; Sarath Meduru; Lucas A Citro; Balázs Bognár; Mahmood Khan; Tamás Kálai; Kálmán Hideg; Periannan Kuppusamy; Chittoor B Sai-Sudhakar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-21
Journal Detail:
Title:  Hypertension     Volume:  61     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-14     Completed Date:  2013-04-12     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  593-601     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Down-Regulation / physiology*
Heart Failure / complications*,  drug therapy,  metabolism,  ultrasonography
Humans
Hypertension, Pulmonary / drug therapy,  etiology*,  metabolism,  pathology,  ultrasonography
Lung / blood supply,  drug effects,  metabolism,  pathology
Male
Microvessels / drug effects,  metabolism
Muscle, Smooth, Vascular / drug effects,  metabolism
Oxidative Stress / drug effects
PTEN Phosphohydrolase / biosynthesis*
Peroxynitrous Acid / analysis,  metabolism*
Piperidones / therapeutic use
Pulmonary Artery / drug effects,  metabolism
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
EB006153/EB/NIBIB NIH HHS; HL095066/HL/NHLBI NIH HHS; R01 EB006153/EB/NIBIB NIH HHS; R21 HL095066/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/(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); 0/Piperidones; 14691-52-2/Peroxynitrous Acid; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.48/Pten protein, rat; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections

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