Article

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.

2 Followers
 · 
89 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary artery hypertension (PAH) is characterized by vascular remodeling, high pulmonary blood pressure, and right ventricular hypertrophy. Oxidative stress, inflammation and pulmonary artery remodeling are important components in PAH. Ellagic acid (EA) is a phenolic compound with anti-oxidative, anti-inflammatory, and anti-proliferative properties. This study aimed to investigate whether EA could prevent the development of monocrotaline (MCT)-induced PAH in rats.Methods Male Sprague-Dawley rats received EA (30 and 50 mg/kg/day) or vehicle one day after a single-dose of monocrotaline (MCT, 60 mg/kg). Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were assessed 4 weeks later. Activation of the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome pathway in the lungs was assessed using western blot analysis.ResultsMCT induced PAH, oxidative stress, and NLRP3 inflammasome activation in vehicle-treated rats. EA reduced right ventricle systolic pressure, the right ventricular hypertrophy and the wall thickness/external diameter ratio of the pulmonary arteries compared with vehicle. EA also inhibited the MCT-induced elevation of oxidative stress, NLRP3, caspase-1, IL-β in the lungs and the elevated levels of brain natriuretic peptide (BNP) and inflammatory cytokines in serum.Conclusions Ellagic acid ameliorates monocrotaline-induced pulmonary artery hypertension via exerting its anti-oxidative property inhibiting NLRP3 inflammasome signal pathway in rats.
    International Journal of Cardiology 11/2014; 180. DOI:10.1016/j.ijcard.2014.11.161 · 6.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Substantial experimental evidence suggests the usefulness of antioxidants for the treatment of various forms of pulmonary hypertension. However, no recommendations have yet been made if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Our understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins to the modulation of vascular oxidases such as NAD(P)H oxidases. These oxidases and their products regulate not only pulmonary vascular tone and intimal and smooth muscle thickening, but also modulate the adaptation of the right ventricle to increased afterload. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-reactive oxygen species activation in the pathogenesis and treatment of pulmonary hypertension. The purpose of this Forum on Pulmonary Hypertension is to summarize the available pre-clinical information, which may aid in designing and conducting future randomized clinical trials for evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension. The complexity of oxidative pathways contributed to the tremendous difficulties and challenges in selecting agents, doses and designing clinical trials. Further studies using human, animal, and cell culture models may be needed to define optimal trials. This Forum on Pulmonary Hypertension should stimulate new thinking and provide essential background information to better define the challenges of developing successful randomized clinical trials in the near future.
    Antioxidants & Redox Signaling 01/2013; 18(14). DOI:10.1089/ars.2013.5193 · 7.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hyperhomocysteinemia (hHcys) is an important pathogenic factor contributing to the progression of end-stage renal disease. Recent studies have demonstrated the implication of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated NLRP3 inflammasome activation in the development of podocyte injury and glomerular sclerosis during hHcys. However, it remains unknown which reactive oxygen species (ROS) are responsible for this activation of NLRP3 inflammasomes and how such action of ROS is controlled. The present study tested the contribution of common endogenous ROS including superoxide (O2(•-)), hydrogen peroxide (H2O2), and hydroxyl radical ((•)OH) to the activation of NLRP3 inflammasomes in mouse podocytes and glomeruli. In vitro, confocal microscopy and size exclusion chromatography demonstrated that dismutation of O2(•-) by 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL) and decomposition of H2O2 by catalase prevented Hcys-induced aggregation of NLRP3 inflammasome proteins and inhibited Hcys-induced caspase-1 activation and IL-1β production in mouse podocytes. However, (•)OH scavenger tetramethylthiourea (TMTU) had no significant effect on either Hcys-induced NLRP3 inflammasome formation or activation. In vivo, scavenging of O2(•-) by TEMPOL and removal of H2O2 by catalase substantially inhibited NLRP3 inflammasome formation and activation in glomeruli of hHcys mice as shown by reduced colocalization of NLRP3 with ASC or caspase-1 and inhibition of caspase-1 activation and IL-1β production. Furthermore, TEMPOL and catalase significantly attenuated hHcys-induced glomerular injury. In conclusion, endogenously produced O2(•-) and H2O2 primarily contribute to NLRP3 inflammasome formation and activation in mouse glomeruli resulting in glomerular injury or consequent sclerosis during hHcys.
    Free Radical Biology and Medicine 10/2013; 67. DOI:10.1016/j.freeradbiomed.2013.10.009 · 5.71 Impact Factor
Show more