Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
Department of Experimental Medical Science, University of Lund, Sölveg 19, Lund, Sweden.
Atherosclerosis. 2017 Feb;257:64-70. doi: 10.1016/j.atherosclerosis.2016.12.022. Epub 2016 Dec 23.
Chronic kidney disease leads to uremia and markedly accelerates atherosclerosis. Phenotypic modulation of smooth muscle cells (SMCs) in the arterial media plays a key role in accelerating atherogenesis. The aim of this study was to investigate whether uremia per se modulates the phenotype of aortic SMCs in vivo.
Moderate uremia was induced by 5/6 nephrectomy in apolipoprotein E knockout (ApoE) and wildtype C57Bl/6 mice. Plasma analysis, gene expression, histology, and myography were used to determine uremia-mediated changes in the arterial wall.
Induction of moderate uremia in ApoE mice increased atherosclerosis in the aortic arch en face 1.6 fold (p = 0.04) and induced systemic inflammation. Based on histological analyses of aortic root sections, uremia increased the medial area, while there was no difference in the content of elastic fibers or collagen in the aortic media. In the aortic arch, mRNA and miRNA expression patterns were consistent with a uremia-mediated phenotypic modulation of SMCs; e.g. downregulation of myocardin, α-smooth muscle actin, and transgelin; and upregulation of miR146a. Notably, these expression patterns were observed after acute (2 weeks) and chronic (19 and 30 weeks) uremia, both under normo- and hypercholesterolemic settings. Functionally, aortic constriction was decreased in uremic as compared to non-uremic aorta segments, as measured by myography.
Uremia modulates the phenotype of aortic SMCs as determined by mRNA/miRNA expression, an increased medial area, and decreased aortic contractility. We propose that this phenotypic modulation of SMCs precedes the acceleration of atherosclerosis observed in uremic mice.
慢性肾脏病导致尿毒症，并显著加速动脉粥样硬化。动脉中层平滑肌细胞（SMCs）的表型调节在加速动脉粥样硬化形成中起着关键作用。本研究旨在探讨尿毒症本身是否会调节体内主动脉 SMC 的表型。
通过 5/6 肾切除术在载脂蛋白 E 敲除（ApoE）和野生型 C57Bl/6 小鼠中诱导中度尿毒症。通过血浆分析、基因表达、组织学和肌描记术来确定尿毒症介导的动脉壁变化。
在 ApoE 小鼠中诱导中度尿毒症使主动脉弓额面的动脉粥样硬化增加 1.6 倍（p=0.04）并诱导全身性炎症。基于主动脉根部切片的组织学分析，尿毒症增加了中膜面积，而主动脉中膜的弹性纤维或胶原含量没有差异。在主动脉弓中，mRNA 和 miRNA 的表达模式与尿毒症介导的 SMC 表型调节一致；例如，心肌肌球蛋白、α-平滑肌肌动蛋白和转胶蛋白下调，miR146a 上调。值得注意的是，这些表达模式在急性（2 周）和慢性（19 和 30 周）尿毒症以及正常和高胆固醇血症条件下都有观察到。功能上，与非尿毒症主动脉段相比，尿毒症的主动脉收缩力降低，通过肌描记术测量。
尿毒症通过 mRNA/miRNA 表达、中膜面积增加和主动脉收缩力降低来调节主动脉 SMC 的表型。我们提出，这种 SMC 表型调节先于尿毒症小鼠中观察到的动脉粥样硬化加速。
