Sudden cardiac death is one of the most frequent causes of death at high altitude. It has been reported that the intermittent normobaric hypoxia experienced by patients with obstructive sleep apnea may enhance the development of atherosclerosis. However, the effect of hypobaric hypoxia, which mimics the ambient air at high altitude, in the development of atherosclerosis has not been investigated.
Increased oxidative stress is involved in the development of vascular dysfunction and remodeling. Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in vascular smooth muscle cells (SMCs). To promote the study of the role of UCP2 in vascular diseases, a transgenic mouse model expressing human UCP2 (hUCP2) in vascular SMCs was established. We constructed a plasmid carrying the 2.3 kb rabbit smooth muscle myosin heavy chain promoter and the hUCP2 gene. We used this plasmid to produce transgenic mice by pro-nuclear microinjection. Six offspring were identified as founder mice that were used to establish a transgenic mouse lineage. The transgenic mice showed a significant increase in hUCP mRNA expression in the aorta. Moreover, hUCP2 overexpression inhibited the production of superoxide and increased the bioavailability of nitric oxide (NO). In this study, we established a hUCP2 transgenic mouse model, which will enable further studies on the role of UCP2 in vascular dysfunction and remodeling.
Saturated fatty acids (FA) have been linked to an increased risk of cardiovascular disease. The effects of acipimox, a FA-lowering agent, on palmitate- (an important saturated fatty acid) stimulated atherosclerosis remains to be elucidated. We investigated the effects of acipimox on atherosclerosis in ApoE(-/-) mice fed a palmitate-rich diet. Male ApoE(-/-) mice, 6-8 weeks of age, were randomized into three groups. The animals were fed a normal chow diet in the control group, a diet containing 5% palmitic acid in the palmitate group, and a diet containing 5% palmitic acid and 0.02% acipimox in the acipimox group. The plasma lipid profiles, aortic lesions, plaque collagen content and the expression of matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, and MMP-14 and the tissue inhibitor of MMP (TIMP)-1, and TIMP-2 were determined after a 12-week treatment. The palmitate-rich diet significantly increased plasma FA concentrations (P<0.01), enhanced atherosclerotic lesions (P<0.01), decreased plaque collagen content (P<0.01) and upregulated MMP-2 (P<0.05) in the aorta. Additionally, all of these harmful effects were significantly attenuated by co-treatment with acipimox (P<0.05 or P<0.01). The present study suggests that acipimox attenuates atherosclerosis and enhances plaque stability in ApoE(-/-) mice fed a palmitate-rich diet.
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