PMID- 21850273
OWN - NLM
STAT- MEDLINE
DCOM- 20120202
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 8
DP  - 2011
TI  - Pulmonary oxidative stress is increased in cyclooxygenase-2 knockdown mice with 
      mild pulmonary hypertension induced by monocrotaline.
PG  - e23439
LID - 10.1371/journal.pone.0023439 [doi]
LID - e23439
AB  - The aim of this study was to examine the role of cyclooxygenase-2 (COX-2) and 
      downstream signaling of prostanoids in the pathogenesis of pulmonary hypertension 
      (PH) using mice with genetically manipulated COX-2 expression. COX-2 knockdown 
      (KD) mice, characterized by 80-90% suppression of COX-2, and wild-type (WT) 
      control mice were treated weekly with monocrotaline (MCT) over 10 weeks. Mice 
      were examined for cardiac hypertrophy/function and right ventricular pressure. 
      Lung histopathological analysis was performed and various assays were carried out 
      to examine oxidative stress, as well as gene, protein, cytokine and prostanoid 
      expression. We found that MCT increased right ventricular systolic and pulmonary 
      arterial pressures in comparison to saline-treated mice, with no evidence of 
      cardiac remodeling. Gene expression of endothelin receptor A and thromboxane 
      synthesis, regulators of vasoconstriction, were increased in MCT-treated lungs. 
      Bronchoalveolar lavage fluid and lung sections demonstrated mild inflammation and 
      perivascular edema but activation of inflammatory cells was not predominant under 
      the experimental conditions. Heme oxygenase-1 (HO-1) expression and indicators of 
      oxidative stress in lungs were significantly increased, especially in COX-2 KD 
      MCT-treated mice. Gene expression of NOX-4, but not NOX-2, two NADPH oxidase 
      subunits crucial for superoxide generation, was induced by  approximately 4-fold in both groups 
      of mice by MCT. Vasodilatory and anti-aggregatory prostacyclin was reduced by 
       approximately 85% only in MCT-treated COX-2 KD mice. This study suggests that increased 
      oxidative stress-derived endothelial dysfunction, vasoconstriction and mild 
      inflammation, exacerbated by the lack of COX-2, contribute to the pathogenesis of 
      early stages of PH when mild hemodynamic changes are evident and not yet 
      accompanied by vascular and cardiac remodeling.
FAU - Seta, Francesca
AU  - Seta F
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
FAU - Rahmani, Mahboubeh
AU  - Rahmani M
FAU - Turner, Patricia V
AU  - Turner PV
FAU - Funk, Colin D
AU  - Funk CD
LA  - eng
GR  - MOP-79459/Canadian Institutes of Health Research/Canada
GR  - MOP-93689/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110805
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 73077K8HYV (Monocrotaline)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
SB  - IM
MH  - Animals
MH  - Cyclooxygenase 2/genetics/*metabolism
MH  - Female
MH  - Hypertension, Pulmonary/*chemically induced/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Monocrotaline/*toxicity
MH  - Oxidative Stress/*drug effects/genetics
PMC - PMC3151294
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/08/19 06:00
MHDA- 2012/02/03 06:00
PMCR- 2011/08/05
CRDT- 2011/08/19 06:00
PHST- 2011/03/23 00:00 [received]
PHST- 2011/07/18 00:00 [accepted]
PHST- 2011/08/19 06:00 [entrez]
PHST- 2011/08/19 06:00 [pubmed]
PHST- 2012/02/03 06:00 [medline]
PHST- 2011/08/05 00:00 [pmc-release]
AID - PONE-D-11-05456 [pii]
AID - 10.1371/journal.pone.0023439 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(8):e23439. doi: 10.1371/journal.pone.0023439. Epub 2011 Aug 5.