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-

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-

Using Naϩ /Ca 2ϩ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca 2ϩ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1 Ϫ/Ϫ homozygous mice die of heart failure before birth, we used NCX1 ϩ/Ϫ heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca 2ϩ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/ reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. Histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca 2ϩ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1 ϩ/ϩ and NCX1 ϩ/Ϫ acute renal failure mice were improved to the same level. These findings strongly support the view that Ca 2ϩ overload via the reverse mode of Na ϩ /Ca 2ϩ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.Renal ischemia is characterized by the depletion of ATP and the development of intracellular acidosis, which alter cellular ionic homeostasis. In particular, elevated intracellular Ca 2ϩ concentration causes cellular injury during ischemia and leads to irreversible renal damage during reperfusion (Schrier et al., 1987). An increase in the intracellular Na ϩ concentration has been shown to correlate with Ca 2ϩ

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