Increased C-C chemokine receptor 2 gene expression in monocytes of severe obstructive sleep apnea patients and under intermittent hypoxia.

BACKGROUND: Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. The chemotaxis and adhesion of monocytes to the endothelium in the early atherosclerosis is important. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the chemotaxis and adhesion of monocytes. METHODS: Peripheral blood was sampled from 54 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of C-C chemokine receptor 2 (CCR2). The effect of intermittent hypoxia on the regulation and function of CCR2 was investigated on THP-1 monocytic cells and monocytes. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. Transwell filter migration assay and cell adhesion assay were performed to study the chemotaxis and adhesion of monocytes. RESULTS: Monocytic CCR2 gene expression was found to be increased in severe OSA patients and higher levels were detected after sleep. Intermittent hypoxia increased the CCR2 expression in THP-1 monocytic cells even in the presence of TNF-α and CRP. Intermittent hypoxia also promoted the MCP-1-mediated chemotaxis and adhesion of monocytes to endothelial cells. Furthermore, inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of monocytic CCR2 expression by intermittent hypoxia. CONCLUSIONS: This is the first study to demonstrate the increase of CCR2 gene expression in monocytes of severe OSA patients. Monocytic CCR2 gene expression can be induced under intermittent hypoxia which contributes to the chemotaxis and adhesion of monocytes.

Increased matrix metalloproteinases-9 after sleep in plasma and in monocytes of obstructive sleep apnea patients.

AIMS: Obstructive sleep apnea is known to be a risk factor of coronary artery disease. Matrix metalloproteinases (MMPs) contribute to the instability and rupture of atherosclerotic plaque and acute coronary syndrome. The present study aimed to determine the correlation of MMPs including MMP-1, -2, -3 and -9 with the severity of obstructive sleep apnea (OSA). MAIN METHODS: Peripheral blood was sampled before and after overnight polysomnography study from OSA patients. Plasma was processed for ELISA and zymography. Monocytes were isolated from peripheral blood and RNA was prepared for RT/real-time PCR. KEY FINDINGS: The plasma level of MMP-9, but not MMP-1, -2, and -3 and TIMP-1 was remarkably increased in OSA patients. The plasma MMP-9 level was considerably higher after sleep and the net difference was most significant in patients with severe OSA. The plasma MMP-9 activity was also demonstrated to be significantly higher after sleep. The mRNA expression of MMP-9 in monocytes not only correlated well to the plasma MMP-9 level in the patients, but also was found to be significantly higher in patients with severe OSA. SIGNIFICANCE: This study for the first time proves that the increase of plasma MMP-9 level in OSA patients is likely due to the up-regulated MMP-9 mRNA expression of monocytes in the peripheral blood.