BQ123 Stimulates Skeletal Muscle Antioxidant Defense via Nrf2 Activation in LPS-Treated Rats

Abstract

Little is understood of skeletal muscle tissue in terms of oxidative stress and inflammation. Endothelin-1 is an endogenous, vasoconstrictive peptide which can induce overproduction of reactive oxygen species and proinflammatory cytokines. The aim of this study was to evaluate whether BQ123, an endothelin-A receptor antagonist, influences the level of TNF-α, IL-6, SOD-1, HO-1, Nrf2 mRNA, and NF-κB subunit RelA/p65 mRNA in the femoral muscle obtained from endotoxemic rats. Male Wistar rats were divided into 4 groups (n = 6) and received iv (1) saline (control), (2) LPS (15 mg/kg), (3) BQ123 (1 mg/kg), (4) BQ123 (1 mg/kg), and LPS (15 mg/kg, resp.) 30 min later. Injection of LPS led to significant increase in levels of RelA/p65 mRNA, TNF-α, and IL-6, while content of SOD-1, HO-1, and Nrf2 mRNA was unchanged. Administration of BQ123 prior to LPS challenge resulted in a significant reduction in RelA/p65 mRNA, TNF-α, and IL-6 levels, as well as markedly elevated concentrations of SOD-1, HO-1, and Nrf2 mRNA. BQ123 appears to enhance antioxidant defense and prevent production of TNF-α and IL-6 in skeletal muscle of LPS-treated rat. In conclusion, endothelin-A receptor antagonism exerts significant impact on the skeletal muscle favouring anti-inflammatory effects and protection against oxidative stress.

Figure 1

The effect of LPS (15 mg/kg), BQ123 (1 mg/kg), and BQ123 + LPS (1 mg/kg and 15 mg/kg, resp.) on TNF-α (a), IL-6 (b), and RelA/p65 mRNA (c) levels in the rat skeletal muscle. Results are expressed as mean ± SEM. n = 6 per group. ^∗ p < 0.001 versus control; ^∗∗ p < 0.01 versus control; ^∧ p < 0.001 versus LPS; ^∧∧ p < 0.01 versus LPS.

Figure 2

The effect of LPS (15 mg/kg), BQ123 (1 mg/kg), and BQ123 + LPS (1 mg/kg and 15 mg/kg, resp.) on Nrf2 mRNA (a), HO-1 (b), and SOD-1 (c) levels in the rat skeletal muscle. Results are expressed as mean ± SEM. n = 6 per group. ^∗ p < 0.001 versus control; ^∗∗ p < 0.01 versus control; ^∧∧ p < 0.01 versus LPS; ^∧∧∧ p < 0.05 versus LPS.