| Backgrounds：Epidemiological sudyies demonstrated that the risk of sudden cardiac deathin population with repetitive acute ascents to altitude is much higher than at lowaltitude.High altitude environmental make great contribution to the increasedrates of cardiovascular disease.At present,there are a large number of peopleliving at high altitude.Moreover,more and more people go to plateau totravel,live and work.The studies suggested that intermittent normobaric hypoxiaaccelerates atherosclerotic plaque growth in ApoE-/-mice.Salidroside,p-hydroxy-phenethyl-β-D-glucoside,is isolated from Rhodiolarosea and is one of the main active components in Rhodiola species.It has beenwidely used for a long time in Traditional Chinese Medicine.Salidroside hasbeen identified as the most potent ingredient in this medical plant and has beenreported to have various plarmacological properties,including protectheart,antifatigue, antistress and anticancer and so on.But,How has salidrosideaffect to AS in IHH-induced ApoE-/-mice?Now,it still hasn,t been reported.Ourprevious studies suggested that intermittent hypobaric hypoxia promoteatherosclerotic plaque instability in ApoE-/-mice.However,the effects ofsalidroside on the growth of atherosclerotic plaque and plaque stability inIHH-induced ApoE-/-mice are unknown.Objectives:The present study aimed to investigate whether intermittent hypobarichypoxia could accelerate atherosclerosis and promote instability and that can beblocked by treatment with salidroside in ApoE-/-mice.Methods：Male ApoE-/-mice,8weeks of age,were randomized into normal group(control group),intermittent hypobaric hypoxia group (IHH),hypobarichypoxia+salidroside group (intervention group) for12weeks.Mice in IHHgroup and intervention group were exposed to a hypobaric chamer mimickingthe hypobaric hypoxia condition on an altitude of5000m for8hours every day,Each group was fed with same general diet,The intervention group (salidrosidedose30mg/kg/oral gavage),while the control group and IHH group wereadministered distilled water,for12weeks.Then,the following measurementswere performed.1. Plasma parameters such as total cholesterol (TC), triglycerides（TG）,low densitylipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C) and fasting blood glucose (FBG) levels in plasma were measured.2. The atherosclerotic lesions in the aortic roots were examined incross-sections of the aortic origin and were stained with hematoxylin-eosin.3. Paraffin sections were obtained from the aortic roots and the plaquecollagen content was detected using a fast Masson dye kit.4. The expression of matrix metalloproteinase (MMP-2, MMP-3, MMP-9and MMP-14) and the tissue inhibitor of MMP (TIMP-1and TIMP-2) weredetermined by immunohistochemical analysis.5. The expression of (MMP-2, MMP-3, MMP-9and MMP-14) and(TIMP-1and TIMP-2) were determined by Western blot analysis.Results：1. The plasma LDL-C, HDL-C，TG，TC and FBG concentrations were notaffected by the intermittent hypobaric hypoxia or salidroside treatment（P＞0.05）.2. After a12-week treatment, the atherosclerotic plaque size in the aorticroot was increased in intermittent hypobaric hypoxia group compared to thecontrol group (P <0.05). As expected, the plaque sizes in aortic root wereattenuated by co-treatment with salidroside (P<0.05). 3. The collagen content in atherosclerotic plaques in the aortic root wasdecreased in intermittent hypobaric hypoxia mice relative to the plaques in thecontrol mice (P<0.05). Moreover, the intermittent hypobaric hypoxia-induceddecrease in collagen content was reduced by treatment with salidroside (P <0.05).4. MMP-2, MMP-9was significantly upregulated by intermittenthypobaric hypoxia, whereas this effect was attenuated by co-treatment withsalidroside (P<0.05，P<0.01).The intermittent hypobaric hypoxia remarkablydecreased the expression of TIMP-2(P<0.01), which was upregulated byco-treatment with salidroside. There was no distinct staining for MMP-3orTIMP-1in the aortic sections. The protein expression levels of MMP-14werenot affected by intermittent hypobaric hypoxia or salidroside（P＞0.05）.5. To western blot, The protein expression levels of MMP-3,MMP-14andTIMP-1were not affected by intermittent hypobaric hypoxia or salidroside（P＞0.05）.MMP-2, MMP-9was remarkably upregulated by intermittent hypobarichypoxia, whereas this effect was attenuated by co-treatment with salidroside(P<0.05，P<0.01).The intermittent hypobaric hypoxia significantly decreasedthe expression of TIMP-2(P<0.05),which was upregulated by co-treatmentwith salidroside.Conclusions:1. Intermittent hypobaric hypoxia not only remarkably enhances thegrowth of atherosclerotic plaques，but also promotes plaque instability.2. Salidroside significantly alleviates intermittent IHH-induced ApoE-/-mice atherosclerotic lesion development and plaque instability.3. One mechanism by which salidroside could relieve IHH-induced plaqueinstability is in connection with salidroside increased plaque collagen contentand TIMP-2,MMP-2and MMP-9were decreased. |
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