Exercise induces superoxide and NOX4 contribution in endothelium-dependent dilation in coronary arterioles from a swine model of chronic myocardial ischemia

Article

Author: Heaps, Cristine L ; Bray, Jeff F ; Sytha, Sharanee P

Exercise training is an effective, nonpharmacologic therapy and preventative measure for ischemic heart disease. While recent studies have examined reactive oxygen species (ROS) as mediators of exercise training-enhanced coronary blood flow, specific oxidants and their sources have yet to be fully elucidated. We investigated the hypothesis that NADPH oxidase (NOX)-derived superoxide anion would contribute to vasodilation effects in the coronary microcirculation of swine and that these effects would be impaired by chronic ischemia and rescued with exercise training. Adult Yucatan miniature swine were instrumented with an ameroid occluder around the proximal left circumflex coronary artery, resulting in a collateral-dependent myocardial region. Eight weeks post-operatively, swine were randomly assigned to either a sedentary or exercise training (treadmill run; 5 days/week for 14 weeks) protocol. Coronary arterioles were isolated from nonoccluded and collateral-dependent myocardial regions and pressure myography was performed. Exercise training resulted in enhanced endothelium-dependent dilation after occlusion. Scavenging of superoxide via the superoxide dismutase (SOD)-mimetic, tempol, attenuated dilation in both nonoccluded and collateral-dependent arterioles of exercise-trained, but not sedentary swine. NOX1/4 inhibition with GKT136901 attenuated dilation after exercise training but only in collateral-dependent arterioles. High performance liquid chromatography revealed that neither ischemia nor exercise training significantly altered basal or bradykinin-stimulated superoxide levels. Furthermore, superoxide production was not attributable to NOX isoforms nor mitochondria. Immunoblot analyses revealed significantly decreased NOX2 protein after exercise with no differences in NOX1, NOX4, p22phox, SOD proteins. Taken together, these data provide evidence that superoxide and NOX4 independently contribute to enhanced endothelium-dependent dilation following exercise training.

07 Sep 2023·Antioxidants (Basel, Switzerland)

Redox Regulation of Microglial Inflammatory Response: Fine Control of NLRP3 Inflammasome through Nrf2 and NOX4.

Article

Author: Valencia, Inés ; Romero, Alejandro ; Egea, Javier ; López-Muñoz, Francisco ; Farré-Alins, Víctor ; Cuadrado, Antonio ; Lopez-Rodriguez, Ana Belen ; Narros-Fernández, Paloma ; Casas, Ana I ; Álvarez-Rubal, María ; Palomino-Antolín, Alejandra ; Ramos, Eva ; Decouty-Pérez, Céline

The role of inflammation and immunity in the pathomechanism of neurodegenerative diseases has become increasingly relevant within the past few years. In this context, the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the activation of inflammatory responses by promoting the maturation and secretion of pro-inflammatory cytokines such as interleukin-1β and interleukin-18. We hypothesized that the interplay between nuclear factor erythroid 2-related factor 2 (Nrf2) and NADPH oxidase 4 (NOX4) may play a critical role in the activation of the NLRP3 inflammasome and subsequent inflammatory responses. After priming mixed glial cultures with lipopolysaccharide (LPS), cells were stimulated with ATP, showing a significant reduction of IL1-β release in NOX4 and Nrf2 KO mice. Importantly, NOX4 inhibition using GKT136901 also reduced IL-1β release, as in NOX4 KO mixed glial cultures. Moreover, we measured NOX4 and NLRP3 expression in wild-type mixed glial cultures following LPS treatment, observing that both increased after TLR4 activation, while 24 h treatment with tert-butylhydroquinone, a potent Nrf2 inducer, significantly reduced NLRP3 expression. LPS administration resulted in significant cognitive impairment compared to the control group. Indeed, LPS also modified the expression of NLRP3 and NOX4 in mouse hippocampus. However, mice treated with GKT136901 after LPS impairment showed a significantly improved discrimination index and recovered the expression of inflammatory genes to normal levels compared with wild-type animals. Hence, we here validate NOX4 as a key player in NLRP3 inflammasome activation, suggesting NOX4 pharmacological inhibition as a potent therapeutic approach in neurodegenerative diseases.

01 Jan 2023·Gastric Cancer

IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC

Article

Author: Park, Suyoung ; Kwon, Hyo-Jung ; Hong, Eun-Ju ; Rho, Jinhyung ; Cho, Young-Eun ; Kang, Jee Hyun ; Won, Young-Suk

AbstractBackgroundGastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC.MethodsGC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms.ResultsDeletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues.ConclusionOur results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.

100 Deals associated with GKT-136901

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Discovery	IT	University of Salerno	31 Aug 2023
Inflammation	Discovery	IT	University of Salerno	31 Aug 2023

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