| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Hiroshi The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (10361487)
YAMAGUCHI Yasuhiro The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (60376473)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Obstructive sleep apnea syndrome (OSAS) is recently recognized as a risk factor for cardiovascular disorders and metabolic syndrome. OSAS is related to obesity, insulin resistance, and diabetes mellitus. In addition, leptin and insulin levels were elevated in patients with OSAS independently of obesity, and visceral fat was the primary parameter linked with sleep apnea. The association of OSAS with insulin resistance and diabetes type 2 has been confirmed. Adiponectin is a hormone secreted by adipocytes that acts as an antidiabetic and antiatherogenic adipocytokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance, and type 2 diabetes. We have found that plasma level of adiponectin is decreased in OSAS patients compared with that in obese control subjects without OSAS. The level of adiponectin is associated with the severity of OSAS as indicated by apnea-hypopnea index (AHI), rather than obesity indexed as body mass index. The lower adipo
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nectin level is also associated with increased levels of hsCRP and IL-6.
At the inflammatory point of view, the levels of TNF-, IL-6, hsCRP, adhesion molecules, and monocyte chemoattractant protein-1 were markedly and significantly elevated in patients with sleep apnea than those in normal control subjects.89 IL-6 and hsCRP levels were independently associated with OSAS severity as indicated by the AHI. In addition, hsCRP level is associated with visceral adipose tissue and is significantly associated with the components of insulin resistance syndrome. These data support the belief that inflammatory processes and metabolic syndrome are activated in atherosclerotic lesions in patients with OSAS. C-reactive protein and other inflammatory cytokines accelerate the progression of atherosclerosis in patients with OSAS. In addition, increase in circulating levels of adenosine and urinary uric acid in patients with obstructive sleep apnea are implicated with increased production of reactive oxygen species. Activation of redox-sensitive gene expression is suggested by the increase in some protein products of these genes, including vascular endothelial growth factor, erythropoietin, endothelin-1, inflammatory cytokines, and adhesion molecules. These results implicate the participation of redox-sensitive transcription factors as hypoxia-inducible factor-1, activator protein-1 and nuclear factor-B.
Importantly, the elevated levels of atherogenic inflammatory mediators were improved by the OSAS-specific treatment such as nasal continuous positive airway pressure. Thus, OSAS plays a crucial role in metabolic syndrome and systemic inflammatory disorders. Furthermore, the hypoxic stress caused by obstructive sleep apnea increased circulating adrenomedullin (ADM) levels in untreated OSAS. The long-term CPAP decreased both the magnitude of arterial oxygen desaturation and plasma ADM levels in the patients. The long-term oxygen therapy also reduced OSAS-induced nocturnal hypoxemia and plasma adrenomedullin levels in patients with OSAS Less
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