Document Detail

Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome.
MedLine Citation:
PMID:  23240585     Owner:  NLM     Status:  MEDLINE    
AIMS: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species, such as superoxide (O(2)(•-)), contribute to the pathogenesis of PH and vascular responses, including vascular remodeling and inflammation. This study sought to investigate the protective role of a pharmacological catalytic antioxidant, a superoxide dismutase (SOD) mimetic (MnTE-2-PyP), in hypoxia-induced PH, vascular remodeling, and NALP3 (NACHT, LRR, and PYD domain-containing protein 3)-mediated inflammation.
RESULTS: Mice (C57/BL6) were exposed to hypobaric hypoxic conditions, while subcutaneous injections of MnTE-2-PyP (5 mg/kg) or phosphate-buffered saline (PBS) were given 3× weekly for up to 35 days. SOD mimetic-treated groups demonstrated protection against increased right ventricular systolic pressure, indirect measurements of pulmonary artery pressure, and RV hypertrophy. Vascular remodeling was assessed by Ki67 staining to detect vascular cell proliferation, α-smooth muscle actin staining to analyze small vessel muscularization, and hyaluronan (HA) measurements to assess extracellular matrix modulation. Activation of the NALP3 inflammasome pathway was measured by NALP3 expression, caspase-1 activation, and interleukin 1-beta (IL-1β) and IL-18 production. Hypoxic exposure increased PH, vascular remodeling, and NALP3 inflammasome activation in PBS-treated mice, while mice treated with MnTE-2-PyP showed an attenuation in each of these endpoints.
INNOVATION: This study is the first to demonstrate activation of the NALP3 inflammasome with cleavage of caspase-1 and release of active IL-1 β and IL-18 in chronic hypoxic PH, as well as its attenuation by the SOD mimetic, MnTE-2-PyP.
CONCLUSION: The ability of the SOD mimetic to scavenge extracellular O(2)(•-) supports our previous observations in EC-SOD-overexpressing mice that implicate extracellular oxidant/antioxidant imbalance in hypoxic PH and implicates its role in hypoxia-induced inflammation.
Leah R Villegas; Dylan Kluck; Carlie Field; Rebecca E Oberley-Deegan; Crystal Woods; Michael E Yeager; Karim C El Kasmi; Rashmin C Savani; Russell P Bowler; Eva Nozik-Grayck
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-05
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  18     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-05     Completed Date:  2013-10-22     Revised Date:  2014-05-13    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1753-64     Citation Subset:  IM    
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MeSH Terms
Carrier Proteins / genetics,  metabolism*
Caspase 1 / metabolism
Gene Expression
Hypertension, Pulmonary / etiology*,  prevention & control
Inflammasomes / metabolism*
Interleukin-18 / metabolism
Interleukin-1beta / metabolism
Metalloporphyrins / metabolism*,  pharmacology
Pulmonary Artery / drug effects,  metabolism*,  pathology*
Superoxide Dismutase / metabolism
Grant Support
Reg. No./Substance:
0/CIAS1 protein, mouse; 0/Carrier Proteins; 0/Inflammasomes; 0/Interleukin-18; 0/Interleukin-1beta; 0/Metalloporphyrins; 0/manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; EC Dismutase; EC 1

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