Hayashi Tetsuya, Yamashita Chika, Matsumoto Chika, Kwak Chol-Jun, Fujii Kiwako, Hirata Tomoko, Miyamura Masatoshi, Mori Tatsuhiko, Ukimura Akira, Okada Yoshikatsu, Matsumura Yasuo, Kitaura Yasushi
Department of Internal Medicine III, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, Japan.
Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2197-203. doi: 10.1152/ajpheart.91496.2007. Epub 2008 Mar 7.
Intermittent hypoxia due to sleep apnea syndrome is associated with cardiovascular diseases. However, the precise mechanisms by which intermittent hypoxic stress accelerates cardiovascular diseases are largely unclear. The aim of this study was to investigate the role of gp91(phox)-containing NADPH oxidase in the development of left ventricular (LV) remodeling induced by intermittent hypoxic stress in mice. Male gp91(phox)-deficient (gp91(-/-)) mice (n = 26) and wild-type (n = 39) mice at 7-12 wk of age were exposed to intermittent hypoxia (30 s of 4.5-5.5% O(2) followed by 30 s of 21% O(2) for 8 h/day during daytime) or normoxia for 10 days. Mean blood pressure and LV systolic and diastolic function were not changed by intermittent hypoxia in wild-type or gp91(-/-) mice, although right ventricular systolic pressure tended to be increased. In wild-type mice, intermittent hypoxic stress significantly increased the diameter of cardiomyocytes and interstitial fibrosis in LV myocardium. Furthermore, intermittent hypoxic stress increased superoxide production, 4-hydroxy-2-nonenal protein, TNF-alpha and transforming growth factor-beta mRNA, and NF-kappaB binding activity in wild-type, but not gp91(-/-), mice. These results suggest that gp91(phox)-containing NADPH oxidase plays a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling through an increase of oxidative stress.
睡眠呼吸暂停综合征导致的间歇性缺氧与心血管疾病相关。然而，间歇性低氧应激加速心血管疾病的确切机制在很大程度上尚不清楚。本研究的目的是探讨含gp91(phox)的NADPH氧化酶在小鼠间歇性低氧应激诱导的左心室（LV）重塑发展中的作用。将7-12周龄的雄性gp91(phox)缺陷（gp91(-/-)）小鼠（n = 26）和野生型（n = 39）小鼠暴露于间歇性缺氧（白天每天8小时，4.5-5.5% O(2) 30秒，随后21% O(2) 30秒）或常氧环境中10天。尽管右心室收缩压有升高趋势，但间歇性缺氧对野生型或gp91(-/-)小鼠的平均血压及左心室收缩和舒张功能无影响。在野生型小鼠中，间歇性低氧应激显著增加了左心室心肌细胞直径和间质纤维化程度。此外，间歇性低氧应激增加了野生型小鼠而非gp91(-/-)小鼠的超氧化物生成、4-羟基-2-壬烯醛蛋白、TNF-α和转化生长因子-β mRNA以及NF-κB结合活性。这些结果表明，含gp91(phox)的NADPH氧化酶通过增加氧化应激在间歇性缺氧诱导的左心室重塑病理生理过程中起关键作用。
