Effect Of Hypobaric Hypoxia On As In ApoE Deficient Mice

Atherosclerosis is a progressive arterial disease, which is a major promotingfactor of ischemic heart disease, cerebrovascular disease and peripheralvascular disease. Sudden cardiac death, one of the most common causes ofdeath in the high altitude areas, is also considered associated withatherosclerosis. It has been reported that intermittent normobaric hypoxiaexperienced by patients with obstructive sleep apnea might enhance thedevelopment of atherosclerosis. Studies have shown that hypoxia may affectserum lipid profiles, attenuated endothelial function, increase level ofinflammation，change plaque composition and promote the development ofatherosclerosis. However, compared with the normobaric hypoxia environmentat low altitudes，the effect of hypobaric hypoxia mimicking the ambient air athigh altitude has not been addressed.Objective: In this study, we tested the effect of plateau intermittent hypobarichypoxia on atherosclerosis by means of animal experiments.Methods: In this study, we used a hypobaric chamber with air pump and20female ApoE-deficient mice to establish a atherosclerosis model of thehypobaric hypoxia environment at high altitude.SPF ApoE-deficient mice wererandomly divided into the control group and the IHH group. The two groups ofmice were fed with normal diet, open eating. The control group was always innormoxic environment, while the hypoxic group was put into the low hypobaric tank which simulating the hypobaric hypoxia environment at4000m. Thehypoxic mice received hypoxia intervention for8h/day×8weeks. Wemeasured the body weight of two groups every10days; once every four dayswe recorded the food intake. Then we determined the serum lipids (TC, TG,HDL-c, LDL-c) level using commercial kits, measured the protein expressionof aortic wall matrix metalloproteinases and their tissue inhibitors (MMP-2,MMP-3, MMP-9, MMP-14, TIMP-1and TIMP-2) by immunohistochemistry.Vascular lumen and plaque area of the aortic root were measured by HEstaining. Masson staining were used for the determination of the collagencontent of the plaque. Pictures collected through the microscope to wasmeasured the area of the vessel lumen, the percentage of plaque area and thetarget protein percentage of positive area using Image-Proplus6.0professionalimage analysis software. Data are presented as mean±SEM, and statisticalanalysis using SPSS10.5software unpaired t-test, p <0.05indicates thedifference between the two groups is significant.Results:1. We found that the body weight of hypoxia mice was significantly lowerthan the control group(p＜0.05), despite the food intake did not differsignificantly(p>0.05).2. The serum lipid level, including TC, TG, HDL-c, LDL-c did not differsignificantly between the IHH group and the control group（p＞0.05）.3. There was also no difference between two groups in the areas of the aortic root lumen（p＞0.05）.4. HE staining of paraffin sections of the plaques on the aortic root and OilRed O stain of the aorta showed the plaque size did not differ significantlybetween two groups（p＞0.05）.5. The plaque collagen content of the hypoxic group was significantlylower than the control group.6. Compared with the control mice, MMP-9was significantly higher in theIHH group of mice (p <0.01), TIMP-2was significantly reduced (p <0.01),while MMP-2/3/14and TIMP-1did not change significantly (p>0.05).Conclusion:1. Intermittent hypobaric hypoxia did not change the level of serum lipidcomposition in ApoE-deficient mice, but body weight was significantlyreduced.2. IHH had no effect on plaque size, but changed the balance of MMP/TIMP expression in aorta of ApoE deficient mice, reduced the content ofcollagen in the aortic root plaque, promoted AS plaque instability.