Azidothymidine (AZT) leads to arterial stiffening and intima-media thickening in mice
Azidothymidine (AZT) leads to arterial stiffening and intima-media thickening in mice
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DOI：
10.1016/j.jbiomech.2013.03.021
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发表时间：
2013-05-31
影响因子：
2.4
通讯作者：
Gleason, Rudolph L., Jr.
中科院分区：
文献类型：
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作者：
Hansen, Laura;Parker, Ivana;Gleason, Rudolph L., Jr.
接受高效抗逆转录病毒治疗（HAART）的艾滋病毒阳性患者显示出一些非艾滋病定义的合并症的发病率升高，包括心血管疾病。鉴于HAART方案包含至少三种药物的组合，疾病管理通常需要调整这些方案，并且独立于HAART的艾滋病毒也在合并疾病的发展中发挥作用，从临床数据确定特定HAART药物和艾滋病毒感染本身的作用仍然具有挑战性。为了描述特定的介质和疾病的潜在机制，需要体外和体内动物模型，同时需要临床数据。鉴于其低廉的成本，azidothymidine （AZT）是发展中国家大部分HAART治疗患者的支柱，而发展中国家是全球艾滋病毒负担的主要来源。本研究的目的是验证AZT可导致小鼠动脉硬化和内膜-中膜增厚等亚临床标志物的动脉粥样硬化改变的假设。用AZT （100 mg/kg）或对照药灌胃野生型FVB/N小鼠35 d。与对照组相比，AZT小鼠颈总动脉和肾上动脉的圆柱形双轴生物力学试验显示动脉硬化。多光子显微镜和组织学显示AZT导致内膜-中膜厚度增加。这些数据与组织蛋白酶酶谱测定的弹性蛋白含量降低和蛋白酶活性增加有关；在胶原含量或组织、体内轴向拉伸或开口角度方面没有观察到差异。因此，本研究提示AZT药物对动脉粥样硬化亚临床标志物的发展有显著影响。(C) 2013 Elsevier Ltd.版权所有。
HIV positive patients on highly active antiretroviral therapy (HAART) have shown elevated incidence of a number of non-AIDS defining co-morbidities, including cardiovascular disease. Given that HAART regimens contain a combination of at least three drugs, that disease management often requires adjustment of these regimens, and HIV, independent of HAART, also plays a role in development of co-morbidities, determining the role of specific HAART drugs and HIV infection itself from clinical data remains challenging. To characterize specific mediators and underlying mechanisms of disease, in vitro and in vivo animal models are required, in parallel with clinical data. Given its low cost azidothymidine (AZT) contributes to the backbone of a large proportion of HAART treated patients in the developing world where much of the global burden of HIV resides. The goal of this study was to test the hypothesis that AZT can lead to proatherogenic changes including the subclinical markers of arterial stiffening and intima-media thickening in mice. AZT (100 mg/kg) or vehicle was administered to wild-type FVB/N mice via oral gavage for 35 days. Cylindrical biaxial biomechanical tests on the common carotid arteries and suprarenal aortas exhibited arterial stiffening in AZT mice compared to controls. Multiphoton microscopy and histology demonstrated that AZT led to increased intima-media thickness. These data correlated with decreased elastin content and increased protease activity as measured by cathepsin zymography; no differences were observed in collagen content or organization, in vivo axial stretch, or opening angle. Thus, this study suggests the drug AZT has significant effects on the development of subclinical markers of atherosclerosis. (C) 2013 Elsevier Ltd. All rights reserved.