The Institute of Endocrinology, Metabolism, and Hypertension, Tel Aviv-Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University, 6 Weizmann Street, 64239 Tel Aviv, Israel.
PPAR Res. 2014;2014:124583. doi: 10.1155/2014/124583. Epub 2014 Jan 22.
Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPAR α in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPAR α (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, P = 0.002. This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, P < 0.01. L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPAR α contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids.
内皮型一氧化氮合酶 (eNOS) 的抑制通过损害血管紧张素 II (AII) 和 NO 之间的平衡加速了载脂蛋白 E 基因敲除 (ApoE-null) 小鼠的动脉粥样硬化。我们之前的数据表明，过氧化物酶体增殖物激活受体 α (PPAR α) 在肾素-血管紧张素系统 (RAS) 的有害作用中发挥作用。我们检验了一个假设，即缺乏 PPAR α 的 ApoE 基因敲除 (DKO) 小鼠对一氧化氮合酶抑制的致动脉粥样硬化作用具有抗性。用低剂量 L-NAME 抑制 12 周后，DKO 小鼠的主动脉窦斑块面积恶化仅为 23%，而 ApoE 基因敲除小鼠则恶化了 23%，差异具有统计学意义 (P = 0.002)。这伴随着活性氧 (ROS-) 生成的主动脉 NADPH 氧化酶活性的增加（AII 的靶点，与 Nox1 表达平行）和致动脉粥样硬化的 iNOS 增加了 10 倍，P < 0.01。L-NAME 还导致 ApoE 基因敲除小鼠的主动脉肾素和血管紧张素原 mRNA 水平增加了一倍，但 DKO 小鼠没有增加，而且它只在 DKO 小鼠中上调了 eNOS。这些数据表明，在 ApoE 基因敲除小鼠中，PPAR α 促进了 L-NAME 诱导的未受抑制的 RAS/AII 作用的致动脉粥样硬化效应，这种效应与 Nox1 和 iNOS 的诱导有关，与血压和血清脂质无关。
