Current molecular medicine · 2026
Inhibition of NOX2 Prevents Impairment of Cardiovascular Response and Inflammatory Tissue Injury Mediated by Nitrosative/ Oxidative Stress in the Lipopolysaccharide-Induced Septic Shock Model in Rats.
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Kara Lutfiye, Elosman Muhammed Ahmed-Reda, Senol Sefika Pinar, İkiz Elif, Didani Parinaz Amini, Kara Tuba, Tunctan Bahar
Аннотация
INTRODUCTION: It is unknown whether inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2 has protective effects against the impaired cardiovascular response and inflammatory tissue injury mediated by nitrosative/ oxidative stress in bacterial septic shock. Therefore, using the NOX2 inhibitor NOX2ds-stat, the effects of NOX2 inhibition on cardiovascular response were explored in a rat septic shock model induced by lipopolysaccharide (LPS), in relation to cardiovascular/renal inflammatory tissue injury.
METHODS: Mean arterial pressure and heart rate were obtained non-invasively using a tail cuff device in rats before and at 1, 2, 3, and 4 hours after injection of saline or LPS. The rats were treated with NOX2ds-stat (0.1, 0.3, or 1 mg/kg) 1 hour following saline or LPS injection. The diazotization method was used to measure nitrite levels in the sera and cardiovascular/renal tissues. The changes in tissue expression of proteins and/or their phosphorylation status related to nuclear factor (NF)-κB/inducible nitric oxide synthase (iNOS)- and NOX2-mediated nitrosative/oxidative stress, as well as peroxisome proliferator-activated receptor (PPAR) α/β/γ, were assessed by the immunoblotting method. Using hematoxylin and eosin staining, histopathological changes in the tissues were evaluated.
RESULTS: A decrease in blood pressure by 48 mmHg and an increase in heart rate by 112 bpm were observed 4 hours after LPS injection. While the expression/ phosphorylation of gp91phox, p47phox, 3-nitrotyrosine, NF-κB p65, iNOS, Vasodilator- Stimulated Phosphoprotein (VASP), and interleukin (IL)-1β proteins was enhanced in the thoracic aorta, renal artery, heart, and kidney tissues, in addition to the levels of nitrite in the sera and tissues of LPS-injected animals, the expression/phosphorylation of endothelial nitric oxide synthase (eNOS), PPARα, PPARβ, and PPARγ was decreased. The LPS-induced changes were ameliorated by NOX2ds-stat (1 mg/kg). NOX2ds-stat also attenuated the LPS-induced increase in scores reflecting inflammatory tissue injury.
DISCUSSION: These findings indicate that selective inhibition of NOX2 prevents both impairment of cardiovascular response and cardiovascular/renal tissue injury, presumably through suppression of NF-κB/iNOS- and NOX2-mediated nitrosative/ oxidative stress associated with increased expression of anti-inflammatory PPARα/β/γ in the rat septic shock model induced by bacterial LPS. Further studies are required to determine whether NOX2 inhibition benefits patients with septic shock.
CONCLUSION: This study provides novel insights into the pathophysiological mechanisms of septic shock and highlights the potential therapeutic value of targeting NOX2 to improve cardiovascular response and inflammatory tissue injury.
METHODS: Mean arterial pressure and heart rate were obtained non-invasively using a tail cuff device in rats before and at 1, 2, 3, and 4 hours after injection of saline or LPS. The rats were treated with NOX2ds-stat (0.1, 0.3, or 1 mg/kg) 1 hour following saline or LPS injection. The diazotization method was used to measure nitrite levels in the sera and cardiovascular/renal tissues. The changes in tissue expression of proteins and/or their phosphorylation status related to nuclear factor (NF)-κB/inducible nitric oxide synthase (iNOS)- and NOX2-mediated nitrosative/oxidative stress, as well as peroxisome proliferator-activated receptor (PPAR) α/β/γ, were assessed by the immunoblotting method. Using hematoxylin and eosin staining, histopathological changes in the tissues were evaluated.
RESULTS: A decrease in blood pressure by 48 mmHg and an increase in heart rate by 112 bpm were observed 4 hours after LPS injection. While the expression/ phosphorylation of gp91phox, p47phox, 3-nitrotyrosine, NF-κB p65, iNOS, Vasodilator- Stimulated Phosphoprotein (VASP), and interleukin (IL)-1β proteins was enhanced in the thoracic aorta, renal artery, heart, and kidney tissues, in addition to the levels of nitrite in the sera and tissues of LPS-injected animals, the expression/phosphorylation of endothelial nitric oxide synthase (eNOS), PPARα, PPARβ, and PPARγ was decreased. The LPS-induced changes were ameliorated by NOX2ds-stat (1 mg/kg). NOX2ds-stat also attenuated the LPS-induced increase in scores reflecting inflammatory tissue injury.
DISCUSSION: These findings indicate that selective inhibition of NOX2 prevents both impairment of cardiovascular response and cardiovascular/renal tissue injury, presumably through suppression of NF-κB/iNOS- and NOX2-mediated nitrosative/ oxidative stress associated with increased expression of anti-inflammatory PPARα/β/γ in the rat septic shock model induced by bacterial LPS. Further studies are required to determine whether NOX2 inhibition benefits patients with septic shock.
CONCLUSION: This study provides novel insights into the pathophysiological mechanisms of septic shock and highlights the potential therapeutic value of targeting NOX2 to improve cardiovascular response and inflammatory tissue injury.