title: Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Villegas
authors.forename: Dylan
authors.initials: D
authors.lastname: Kluck
authors.forename: Carlie
authors.initials: C
authors.lastname: Field
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Oberley-Deegan
authors.forename: Crystal
authors.initials: C
authors.lastname: Woods
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.forename: Karim C
authors.initials: KC
authors.lastname: El Kasmi
authors.forename: Rashmin C
authors.initials: RC
authors.lastname: Savani
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000517:prevention & control; D000860:Hypoxia; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008665:Metalloporphyrins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D013482:Superoxide Dismutase; D020170:Caspase 1