A critical role for p38 map kinase in NF-κB signaling during intermittent hypoxia/reoxygenation

NF-kappa B-dependent inflammatory gene expression is induced by intermittent hypoxia/reoxygenation (IHR), an event that we have hypothesized may contribute to the cardiovascular pathophysiology associated with obstructive sleep apnoea syndrome (OSAS). Here, we have investigated the cellular signaling mechanisms involved. Using an established endothelial cell in vitro model, we confirm a selective activation of the pro-inflammatory transcription factor NF-kappa B over the adaptive hypoxia-inducible factor-1 (HIF-1) in IHR-stimulated bovine aortic endothelial cells. IHR activates the I-kappa B kinase (IKK) complex, leading to phosphorylation/degradation Of I-kappa B alpha. IHR activates p38 MAPK and pharmacological inhibition of p38 (using SB 203580, 10 mu M) abolishes NF-kappa B activation by IHR. Furthermore, depletion of p38 using siRNA significantly reduces IHR-induced NF-kappa B activity. Thus, IHR activates NF-kappa B in an IKK-dependent manner signaled at least in part via activation of p38 MAPK. (c) 2007 Elsevier Inc. All rights reserved.