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A brief elevation of serum amyloid A is sufficient to increase atherosclerosis.

机译：短暂升高血清淀粉样蛋白A足以增加动脉粥样硬化。

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摘要

Cardiovascular disease is now the leading cause of death worldwide. Serum amyloid A (SAA), a positive acute phase reactant, along with C-reactive protein is used clinically as a marker of cardiovascular disease risk. However, recent data has shed light on a possible causal role of SAA in the development of atherosclerosis, the most pervasive form of cardiovascular disease. Several inflammatory diseases such as diabetes and obesity are known to confer increased risk of developing cardiovascular disease. Individuals with these diseases all have modest but persistent elevation of SAA. To determine if SAA caused the development of atherosclerosis, apoe-/- chow fed mice were injected with either an adenoviral vector expressing human SAA1 (ad-hSAA1), a null adenoviral vector (ad-Null) or saline. Human SAA levels rapidly increased, albeit briefly then returned to baseline within 14 days in mice that received ad-hSAA1. After 16 weeks, mice that received ad-hSAA1 had significantly increased atherosclerosis compared to controls on the aortic intimal surface (p<0.0001), aortic sinus (p<0.05) and the brachiocephalic artery (p<0.05). According to the "response to retention" hypothesis; lipoprotein retention by vascular wall proteoglycans is a key initiating event in the development of atherosclerosis. We previously reported that SAA-stimulated vascular smooth muscle cells expressed biglycan with increased glycosaminoglycan chain length and increased binding affinity for low density lipoprotein. To further test the role of biglycan on the development of atherosclerosis we generated biglycan transgenic mice. These mice were crossed to the ldlr-/- mouse on a C57BL/6 background and fed a pro-atherogenic western diet for 12 weeks. There was a significant increase in atherosclerotic lesion area on the aortic intimal surface (p<0.05) and the aortic sinus (p<0.006), as well as a significant correlation between vascular biglycan content and aortic sinus atherosclerotic lesion area (p<0.0001). These data demonstrate that transiently increased SAA resulted in increased atherosclerosis compared to control mice, possibly via increased vascular biglycan content. In support of this we found that biglycan transgenic mice had significantly increased atherosclerosis compared to wildtype controls, likely through increased lipid retention in the vascular wall.;Keywords: Serum amyloid A, Biglycan, Transforming growth factor-beta, Atherosclerosis.
机译：现在，心血管疾病是全球范围内主要的死亡原因。血清淀粉样蛋白A（SAA）（一种急性急性反应物）与C反应蛋白一起在临床上被用作心血管疾病风险的标志物。但是，最近的数据揭示了SAA在动脉粥样硬化（一种最普遍的心血管疾病形式）的发展中可能起的因果作用。已知几种炎性疾病，例如糖尿病和肥胖症，会增加患心血管疾病的风险。患有这些疾病的个体都有适度但持续的SAA升高。为了确定SAA是否引起动脉粥样硬化的发展，给apoe-/-杂粮喂养的小鼠注射表达人SAA1的腺病毒载体（ad-hSAA1），无效的腺病毒载体（ad-Null）或生理盐水。人类SAA水平迅速升高，尽管随后在接受ad-hSAA1的小鼠中在14天内短暂恢复了基线。 16周后，接受ad-hSAA1的小鼠与主动脉内膜表面（p <0.0001），主动脉窦（p <0.05）和肱头动脉（p <0.05）的对照组相比，动脉粥样硬化明显增加。根据“对保留的反应”假说；血管壁蛋白聚糖对脂蛋白的保留是动脉粥样硬化发展中的关键启动事件。我们以前曾报道说，SAA刺激的血管平滑肌细胞表达双糖链蛋白聚糖，具有增加的糖胺聚糖链长度和对低密度脂蛋白的结合亲和力。为了进一步测试双链蛋白聚糖在动脉粥样硬化发展中的作用，我们生成了双链蛋白聚糖转基因小鼠。将这些小鼠在C57BL / 6背景下与ldlr-/-小鼠杂交，并饲喂促动脉粥样硬化的西方饮食12周。主动脉内膜表面和主动脉窦的动脉粥样硬化病变面积显着增加（p <0.056），并且血管二甘聚糖含量与主动脉窦动脉粥样硬化病变面积之间存在显着相关性（p <0.0001） 。这些数据表明，与对照小鼠相比，短暂增加的SAA可能导致动脉粥样硬化的增加，这可能是由于血管二聚糖含量增加所致。为证明这一点，我们发现与野生型对照相比，biglycan转基因小鼠的动脉粥样硬化明显增加，可能是由于血管壁中脂质的滞留增加。关键词：血清淀粉样蛋白A，Biglycan，转化生长因子-β，动脉粥样硬化。

著录项

  • 作者

    Thompson, Joel C.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Pathology.;Histology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 132 p.
  • 总页数 132
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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