The aim of this study was to investigate the effect of chronic hypoxia on the development and progression of atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. Male and female apoE-KO mice (6 weeks old) and age-and sex-matched wild-type mice were kept under hypoxic conditions (10.0 ± 0.5% O2) in a gas chamber or in room air for 3 weeks. Aortic atherosclerotic plaque was not observed in wild-type mice under normoxic or hypoxic conditions. In the apoE-KO mice, however, hypoxia induced proliferation of smooth muscle cells and plaque formation in the aorta, which were not observed under normoxic conditions. Although sexual dimorphism of the response to hypoxia was not observed, these hypoxia-induced athero-

ITIM-KIR expressing NK cells might confer tolerance to peritoneal endometriotic implants.

Elevated superoxide formation in cardiac extracts of apolipoprotein E-knockout (apoE-KO) mice has beenreported. In addition, we previously reported that hypoxia increased oxidative stress in the aortas of apoE-KO mice, although we did not examine the effect of hypoxia on the heart. The aim of this study was to inves-

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.

Sterol 12 alpha-hydroxylase (CYP8B) is a key enzyme for regulating the cholic acid/chenodeoxycholic acid ratio in bile acid biosynthesis. The hepatic CYP8B level was elevated in streptozotocin-induced diabetic rats, and the elevated CYP8B was suppressed by insulin administration [Ishida, H. et al. (1999) J. Biochem. 126, 19-25]. The streptozotocin-induced elevation of hepatic CYP8B mRNA concomitantly responded to the decrement of the serum insulin level. The CYP8B mRNA level in the cultivated rat hepatoma H4TG cells was strongly suppressed by insulin, although it was affected by dibutyryl cAMP or thyroxine to lesser extents. These observations demonstrate that CYP8B expression is dominantly regulated by the direct action of insulin on hepatocytes. A marked circadian rhythm (maximum at 13:00-16:00 and minimum at 1:00) was observed both on the mRNA level and the activity of CYP8B. This rhythm was shifted from that of cholesterol 7 alpha-hydroxylase, a rate-limiting enzyme of bile acid biosynthesis, showing a maximum at 22:00 and a minimum at 10:00, and this shift might oscillate the cholic acid/chenodeoxycholic acid ratio, which is increased in the late afternoon and decreased at midnight. The rhythm of CYP8B was the inverse of the circadian variation of serum insulin level and was similar to the circadian rhythm of glucose 6-phosphatase. These facts and the potent suppressive effect of insulin on CYP8B indicate that the oscillation of the serum insulin may be a factor in producing the circadian rhythm of CYP8B.

Increased percentage of CD158a(+)NK cells in peripheral blood from women with endometriosis was undiminished by laparoscopic surgery and GnRHa treatment; the persistence of CD158a(+)NK cell excess is probably related to NK cell suppression in endometriosis. This overexpression may represent a risk factor for development of endometriosis and its recurrence after treatments.

No abstract

Abstract-Intermittent hypoxia caused by sleep apnea is associated with cardiovascular disease. Chymase has been reported to play an important role in the development of cardiovascular disease, but it is unclear whether chymase is involved in the pathogenesis of left ventricular remodeling induced by intermittent hypoxia. The aim of this study was to evaluate the effect of a novel chymase inhibitor (NK3201) on hypoxia-induced left ventricular remodeling in mice. Male C57BL/6J mice (9 weeks old) were exposed to intermittent hypoxia or normoxia and were treated with NK3201 (10 mg/kg per day) or the vehicle for 10 days. Left ventricular systolic pressure showed no significant differences among all of the experimental groups. Exposure to intermittent hypoxia increased left ventricular chymase activity and angiotensin II expression, which were both suppressed by treatment with NK3201. Intermittent hypoxia also increased the mean cardiomyocyte diameter, perivascular fibrosis, expression of inflammatory cytokines, oxidative stress, and NADPH-dependent superoxide production in the left ventricular myocardium. These changes were all suppressed by NK3201 treatment. Therefore, chymase might play an important role in intermittent hypoxia-induced left ventricular remodeling, which is independent of the systemic blood pressure. (Hypertension. 2009;54:164-171.)