Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

Abstract

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, a-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-1b) 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 b 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.

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

“…Histological examinations demonstrated the same degree of muscularization and accumulation of collagen in pulmonary arteries compared with WT mice. Hence, although Villegas et al (51) have previously inhibited reactive oxygen species production in alveolar hypoxia and found an association between hypoxiainduced pulmonary hypertension and activation of the NLRP3 inflammasome, NLRP3 seemed to be less important for the development of hypoxia-induced pulmonary hypertension than ASC. A possible explanation for this finding is that ASC is involved in several inflammasomes, such as the Aim2, NLRP1, NLRC4, NLRP6, NLRP7, and NLRP12 inflammasomes (22,38,45), and future studies will have to determine whether these Values are presented as means Ϯ SE.…”

“…Such studies can also provide information regarding putative activators of the inflammasomes, such as reactive oxygen species and endogenous molecules like highmobility group box 1 that act via Toll-like receptor 4 in hypoxia-induced pulmonary hypertension (4,51). Finally, it cannot be excluded that inflammasome-independent effects of ASC may be involved.…”

Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease

“…In mice, hypoxia exposure causes pulmonary hypertension, including increased right ventricular systolic pressure and pulmonary vascular remodeling. These changes were also associated with activation of the NLRP3 inflammasome and caspase-1, as well as increased IL-1b production, and were reversed with a superoxide dismutase mimetic (71). Asc …”

Role of Reactive Oxygen Species in Neonatal Pulmonary Vascular Disease

“…Intratracheal recombinant human SOD also reduces ONOO-mediated protein nitration (103), decreases PDE5 activity, and increases cGMP in the PAs of ventilated PPHN lambs (58), suggesting that antioxidant therapy may improve NO signaling at multiple points in the pathway. The SOD mimetic MnTE-2-PyP attenuates hypoxia-induced pulmonary vascular remodeling and PH in mice (177), and the SOD mimetic M40403 improves NO-mediated relaxation in PAs isolated from hypoxic piglets (60).…”