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: 7.41). 12/2012; 18(14). DOI: 10.1089/ars.2012.4799
Source: PubMed


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.

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.

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.

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.

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    • "Although antioxidants are able to reduce hypoxia - or LPS - induced increase in NLRP3 expression ( Bauernfeind et al . 2011 ; Simard et al . 2013 ; Villegas et al . 2013 ) , cerebral endothelial NLRs remained largely unresponsive to oxidative stress . On the other hand , expression of cerebral endothelial NLRP1 and NLRP3 inflammasome"
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    ABSTRACT: Cerebral endothelial cells (CECs) forming the BBB (blood-brain barrier) are at the interface of the immune and the central nervous systems and thus may play an important role in the functional integration of the two systems. Here we investigated how CECs recognize and respond to pathogen- and damage-associated molecular patterns in order to regulate the functions of the neurovascular unit. First we detected the expression of several NOD-like receptors (NLRs) - including NOD1, NOD2, NLRC4, NLRC5, NLRP1, NLRP3, NLRP5, NLRP9, NLRP10, NLRP12, NLRA and NLRX - in human brain endothelial cells. Inflammatory cytokines, such as IFN-γ, TNF-α, and IL-1β had stimulatory effects on the transcription of many of these receptors. Expression of key inflammasome components (NOD2, NLRP3 and caspase-1) along with caspase-cleaved interleukins IL-1β and IL-33 could be induced by priming with lipopolysaccharide (LPS) and activation with muramyl dipeptide (MDP). In addition, combined treatment with LPS and MDP resulted in IL-1β secretion in a caspase- and ERK1/2 kinase-dependent manner. Our findings demonstrate that NLRs and inflammasomes can be activated in cerebral endothelial cells, which may confer an unexplored role to the BBB in neuroimmune and neuroinflammatory processes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 06/2015; 135(3). DOI:10.1111/jnc.13197 · 4.28 Impact Factor
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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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    International Journal of Cardiology 11/2014; 180. DOI:10.1016/j.ijcard.2014.11.161 · 4.04 Impact Factor
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    Antioxidants & Redox Signaling 01/2013; 18(14). DOI:10.1089/ars.2013.5193 · 7.41 Impact Factor
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