Bro Susanne, Binder Christoph J, Witztum Joseph L, Olgaard Klaus, Nielsen Lars B
Dept. of Nephrology P 2131, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Arterioscler Thromb Vasc Biol. 2007 May;27(5):1080-6. doi: 10.1161/ATVBAHA.107.139634. Epub 2007 Mar 8.
Uremia accelerates atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. We examined whether this effect may be preventable by pharmacological blockade of the renin-angiotensin system (RAS).
Uremia was induced in apoE-/- mice by 5/6 nephrectomy (NX). Treatment with the angiotensin converting enzyme inhibitor enalapril (2 or 12 mg/kg/d) from week 4 to 36 after NX reduced the aortic plaque area fraction from 0.23+/-0.02 (n=20) in untreated mice to 0.11+/-0.01 (n=21) and 0.08+/-0.01 (n=23), respectively (P<0.0001); the aortic plaque area fraction was 0.09+/-0.01 (n=22) in sham-operated controls. Enalapril from week 20 to 44 after NX also retarded the progression of atherosclerosis. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) and concentrations of IgM antibodies against oxidized low density lipoprotein (OxLDL) increased after NX (P<0.01). Enalapril (12 mg/kg/d) attenuated these increases (P<0.05) and reduced aortic expression of vascular cell adhesion molecule (VCAM)-1 mRNA (P<0.05). Atherosclerosis in NX mice was also reduced by losartan (an angiotensin II receptor-blocker), but not when blood pressure was lowered with hydralazine (a non-RAS-dependent vasodilator).
The results suggest that inhibition of RAS abolishes the proatherogenic effect of uremia independent of its blood pressure-lowering effect, possibly because of antiinflammatory and antioxidative mechanisms.
尿毒症会加速载脂蛋白E缺乏（apoE-/-）小鼠的动脉粥样硬化进程。我们研究了通过药物阻断肾素-血管紧张素系统（RAS）是否可以预防这种效应。
通过5/6肾切除术（NX）在apoE-/-小鼠中诱导尿毒症。在NX术后第4周开始至第36周，用血管紧张素转换酶抑制剂依那普利（2或12mg/kg/d）治疗，可使主动脉斑块面积分数分别从未治疗小鼠的0.23±0.02（n = 20）降至0.11±0.01（n = 21）和0.08±0.01（n = 23）（P<0.0001）；假手术对照组的主动脉斑块面积分数为0.09±0.01（n = 22）。在NX术后第20周开始至第44周使用依那普利也延缓了动脉粥样硬化的进展。NX术后血浆可溶性细胞间黏附分子-1（sICAM-1）和血管细胞黏附分子-1（sVCAM-1）水平以及抗氧化型低密度脂蛋白（OxLDL）的IgM抗体浓度升高（P<0.01）。依那普利（12mg/kg/d）减弱了这些升高（P<0.05）并降低了主动脉血管细胞黏附分子（VCAM）-1 mRNA的表达（P<0.05）。氯沙坦（一种血管紧张素II受体阻滞剂）也可减轻NX小鼠的动脉粥样硬化，但使用肼屈嗪（一种非RAS依赖性血管扩张剂）降低血压时则无此作用。
结果表明，抑制RAS可消除尿毒症的促动脉粥样硬化作用，且与其降压作用无关，这可能是由于抗炎和抗氧化机制所致。
