Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome.

University of Colorado, Pediatrics, Aurora, Colorado, United States, , University of Colorado, Cardiovascular Pulmonary Research, Aurora, Colorado, United States
Antioxidants & Redox Signaling (Impact Factor: 7.67). 12/2012; DOI: 10.1089/ars.2012.4799
Source: PubMed

ABSTRACT Aims: Pulmonary hypertension (PH) is characterized by an oxidant/antioxidant imbalance that promotes abnormal vascular responses. Reactive oxygen species (ROS) such as superoxide (O2•-) contribute to the pathogenesis of pulmonary hypertension (PH), and vascular responses including 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 domains-containing protein 3) mediated inflammation. Results: Mice (C57/BL6) were exposed to hypobaric hypoxic conditions while sub-cutaneous injections of MnTE-2-PyP (5mg/kg) or PBS were given 3x weekly for up to 35 days. MnTE-2-PyP treated groups demonstrated protection against increased right ventricular systolic pressure (RVSP) and RV hypertrophy. Vascular remodeling, assessed by vascular cell proliferation (Ki67), small vessel muscularization (α-smooth muscle actin), and extracellular matrix modulation (hyaluronan), was attenuated by MnTE-2-PyP treatment. Hypoxia-induced activation of the NALP3 inflammasome pathway, measured by NALP3 expression, caspase-1 activation, and IL-1β and IL-18 production, was also attenuated by MnTE-2-PyP. 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 pulmonary hypertension, as well as its attenuation by the SOD mimetic, MnTE-2-PyP. Conclusion: The ability of the SOD mimetic to scavenge extracellular O2•- supports our previous observations in EC-SOD overexpressing mice that implicate extracellular oxidant/anti-oxidant imbalance in hypoxic pulmonary hypertension and its role in hypoxia induced inflammation.

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    • "Dysregulation of the oxidant/antioxidant balance impairs vascular tone and contributes to the pathological activation of antiapoptotic and mitogenic pathways, leading to cell proliferation and obliteration of the vasculature [17]. Antioxidant intervention shows protective effects in experimental PAH [14] [15]. However, the underlying mechanism has never been fully understood. "
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