Cassis Lisa A, Gupte Manisha, Thayer Sarah, Zhang Xuan, Charnigo Richard, Howatt Deborah A, Rateri Debra L, Daugherty Alan
Rm. 521b, Wethington Bldg., Graduate Center for Nutritional Sciences, Univ. of Kentucky, Lexington, KY 40536-0200, USA.
Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1660-5. doi: 10.1152/ajpheart.00028.2009. Epub 2009 Feb 27.
Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.
在高脂血症小鼠中输注血管紧张素II（ANG II）会加剧动脉粥样硬化并导致腹主动脉瘤（AAA）的形成。本研究的目的是确定ANG II诱导的高血压对这些血管病变的影响。给雄性载脂蛋白E（apoE）和低密度脂蛋白受体（LDLr）缺陷型小鼠输注ANG II（1000 ng·kg⁻¹·min⁻¹）或去甲肾上腺素（NE；5.6 mg·kg⁻¹·天⁻¹），持续28天。与基线血压（平均动脉压[MAP]，107±2 mmHg）相比，输注ANG II或NE使平均动脉压升高到相似程度（ANG II组，133±2.8；NE组，129±13 mmHg）。输注ANG II的载脂蛋白E缺陷型（apoE⁻/⁻）或低密度脂蛋白受体缺陷型（LDLr⁻/⁻）小鼠的腹主动脉宽度均增加（apoE⁻/⁻：1.4±0.1；LDLr⁻/⁻：1.6±0.2 mm）。相比之下，NE并未改变腹主动脉直径（apoE⁻/⁻：0.91±0.03；LDLr⁻/⁻：0.87±0.02 mm）。同样，与NE相比，输注ANG II的小鼠主动脉弓中的动脉粥样硬化病变要严重得多。在ANG II的亚升压输注速率（500 ng·kg⁻¹·min⁻¹）下，50%的apoE⁻/⁻小鼠发生了腹主动脉瘤。或者，给输注ANG II的apoE⁻/⁻小鼠（1000 ng·kg⁻¹·min⁻¹）施用肼屈嗪（250 mg/l）可降低收缩压（第28天：ANG II组，157±6；ANG II/肼屈嗪组，135±6 mmHg），但不能预防腹主动脉瘤的形成或动脉粥样硬化。这些结果表明，向高脂血症小鼠输注ANG II可诱导腹主动脉瘤并加剧动脉粥样硬化，且与血压升高无关。
