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

doi:10.1016/j.bbrc.2007.02.015

Biochemical and Biophysical Research Communications

Volume 355, Issue 3, 13 April 2007, Pages 728-733

https://doi.org/10.1016/j.bbrc.2007.02.015 Get rights and content

Abstract

NF-κB-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-κB over the adaptive hypoxia-inducible factor-1 (HIF-1) in IHR-stimulated bovine aortic endothelial cells. IHR activates the I-κB kinase (IKK) complex, leading to phosphorylation/degradation of I-κBα. IHR activates p38 MAPK and pharmacological inhibition of p38 (using SB 203580, 10 μM) abolishes NF-κB activation by IHR. Furthermore, depletion of p38 using siRNA significantly reduces IHR-induced NF-κB activity. Thus, IHR activates NF-κB in an IKK-dependent manner signaled at least in part via activation of p38 MAPK.

Section snippets

Experimental procedures

Reagents. Specific antibodies against phosphorylated forms of IκB-α, IKKα (Ser180)/IKKβ (Ser181), p38 MAPK, ERK1/2 MAPK, JNK, and Akt (Ser473) and against total proteins IKKα, IKKβ, p38 MAPK, ERK1/2 MAPK, JNK, and Akt were purchased from Cell Signaling Technology, Inc., (Beverley, MA, USA). Anti-IκB-α was obtained from Upstate biotechnology, (Lake Placid, NY, USA). SB 203580 (Calbiochem, San Diego, CA, USA) was reconstituted in dimethyl sulfoxide.

Cell culture and intermittent hypoxia exposure.

IHR activates NF-κB in BAEC

We previously demonstrated selective activation of NF-κB by IHR in HeLa cells⁵. Using the same model of IHR, we confirm this observation in BAEC endothelial cells (Fig. 1). IHR activated NF-κB in a dose-dependent manner with a maximum response at 16 cycles (173 ± 78% increase over normoxia, p = 0.011). Importantly, while the response of the NF-κB-dependent reporter to IHR is modest in comparison to a cytokine-mediated response, it reflects a relatively low number of cycles of intermittent hypoxia

Discussion

Obstructive sleep apnoea syndrome is associated with the development of cardiovascular diseases, particularly systemic arterial hypertension, coronary artery disease, congestive cardiac failure and stroke [2], [3], [4]. Effective therapy with continuous positive airway pressure (CPAP) abolishes apnoeas and reduces the cardiovascular morbidity and mortality [25], [26]. However, the treatment is cumbersome and compliance rates are only moderately satisfactory [27]. The pathophysiology underlying

Acknowledgments

This work was supported by grants from the Science Foundation of Ireland and the Health Research Board of Ireland.

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

Abstract

Section snippets

Experimental procedures

IHR activates NF-κB in BAEC

Discussion

Acknowledgments

Chest

Semin. Cancer Biol.

Trends Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Lancet

Chest

Biochem. Biophys. Res. Commun.

Cell Signal

J. Biol. Chem.

The occurrence of sleep-disordered breathing among middle-aged adults

N. Engl. J. Med.

Association of sleep-disordered breathing, sleep apnoea, and hypertension in a large community-based study. Sleep heart health study.

JAMA

Sleep apnoea as an idependent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities

Eur. Respir. J.

Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the sleep heart health study

Am. J. Respir. Crit. Care Med.

Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnoea syndrome

Circulation

Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity

J. Clin. Endocrinol. Metab.

Effects of obstructive sleep apnoea on circulating ICAM-1, IL-8, and MCP-1

J. Appl. Physiol.

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Am. J. Physiol. Cell Physiol.

NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses

Annu. Rev. Immunol.

Phosphorylation meets ubiquitination: the control of NF-κB activity

Annu. Rev. Immunol.