Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice
Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice
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DOI：
10.1097/01.asn.0000088024.72216.2e
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发表时间：
2003-10-01
影响因子：
13.6
通讯作者：
Nielsen, LB
中科院分区：
文献类型：
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作者：
Bro, S;Bentzon, JF;Nielsen, LB
慢性肾功能衰竭(CRF)患者的心血管死亡率增加了10到20倍。慢性肾功能衰竭患者动脉粥样硬化的危险因素丰富。然而，CRF心血管疾病的发病机制尚不清楚。观察CRF对载脂蛋白E基因缺陷雄性小鼠动脉粥样硬化形成的影响。7周龄小鼠接受5/6肾切除(CRF，n=28)、单侧肾切除(UNX，n=24)或不手术(n=23)。22周后，与未做手术的小鼠相比，慢性肾功能衰竭小鼠的主动脉斑块面积分数(0.266+/-0.033比0.045+/-0.006；P<；0.001)、主动脉胆固醇含量(+/-62比100+/-9nmol/cm2内膜表面积；P<；0.001)和主动脉根部斑块面积(205,296+/-22,098比143,662+/-13,302 um(2)；P<；0.05)与未手术的小鼠相比增加。尿毒症小鼠的斑块含有CD11b阳性的巨噬细胞，对硝基酪氨酸有很强的染色。尿毒症和非尿毒症小鼠的收缩压和血浆同型半胱氨酸浓度相似。与未做手术的小鼠相比，慢性肾衰小鼠的血浆尿素和胆固醇浓度分别升高了2.6倍(P<；0.001)和1.5倍(P<；0.001)。两个变量均与主动脉斑块面积分数相关(r(2)=0.50，P<；0.001和r(2)=0.3，P<；0.001)，并相互关联(12=0.5，P<；0.001)。在多元线性回归分析中，只有血浆尿素是主动脉斑块面积分数的显著预测因子。总之，目前的研究结果表明，尿毒症显著加速载脂蛋白E缺陷小鼠的动脉粥样硬化形成。这种影响不能完全用血压、血浆同型半胱氨酸水平或血浆总胆固醇浓度的变化来解释。因此，CRF载脂蛋白E缺陷小鼠是研究尿毒症动脉粥样硬化加速发病机制的新模型。
Cardiovascular mortality is 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis are abundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n = 28), unilateral nephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aortic cholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm 2 intimal surface area; P < 0.001), and, aortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 mum(2); P < 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP and plasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea and cholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001 and r(2) = 0.3, P < 0.001, respectively) and with each other (12 = 0.5, P < 0.001). On multiple linear regression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that uremia markedly accelerates atherogenesis in apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma homocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.