Department of Cardiovascular Physiology, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Cardiovasc Res. 2011 Nov 1;92(2):338-47. doi: 10.1093/cvr/cvr218. Epub 2011 Sep 28.
CD73 (ecto-5'-nucleotidase) is expressed by a broad range of immune cells and attenuates inflammation in several acute disease models. This study therefore explored the role of CD73-derived adenosine in a model of chronic vascular inflammation such as atherogenesis.
CD73(-/-) mice were backcrossed into the apolipoprotein E (ApoE(-/-)) background. In CD73(-/-)/ApoE(-/-) double mutants, atherosclerotic lesion formation was increased by ∼50% compared with ApoE(-/-). However, the cellular composition and extracellular matrix of the plaques did not differ. Surprisingly, we found significant activity and expression of CD73 in the plaque of ApoE(-/-) mice which increased over time. CD73 co-localized with macrophages, Tregs, and cells of mesenchymal origin. Genome-wide microarray analysis of the aorta lacking CD73 revealed upregulation of endothelin-1 (Edn1) mRNA together with changes of genes in lipid metabolism and the Wnt and nuclear factor kappa B pathways. Measurement of plasma levels verified the upregulation of Edn1 in CD73(-/-) and double mutants. Plasma triglycerides (TG) were also found to be significantly elevated in the CD73(-/-)/ApoE(-/-) mice compared with ApoE(-/-) controls.
Lack of CD73 promotes atherogenesis most likely by de-inhibition of resident macrophages and T cells. Elevated Edn1 and TG levels may have contributed. This establishes CD73-derived adenosine as a direct or indirect regulator of atherogenesis.
CD73（外核苷酸酶 5'-）广泛表达于各种免疫细胞，可减轻几种急性疾病模型中的炎症。因此，本研究探讨了 CD73 衍生的腺苷在动脉粥样硬化等慢性血管炎症模型中的作用。
将 CD73（-/-）小鼠与载脂蛋白 E（ApoE（-/-））背景进行回交。与 ApoE（-/-）相比，CD73（-/-）/ApoE（-/-）双突变体的动脉粥样硬化病变形成增加了约 50%。然而，斑块的细胞组成和细胞外基质没有差异。令人惊讶的是，我们发现 ApoE（-/-）小鼠斑块中的 CD73 活性和表达显著增加，且随时间增加。CD73 与巨噬细胞、Treg 和间充质来源的细胞共定位。缺乏 CD73 的主动脉的全基因组微阵列分析显示内皮素-1（Edn1）mRNA 的上调，以及脂质代谢、Wnt 和核因子 kappa B 途径相关基因的变化。对 CD73（-/-）和双突变体的血浆水平测量证实了 Edn1 的上调。还发现 CD73（-/-）/ApoE（-/-）小鼠的血浆甘油三酯（TG）水平明显高于 ApoE（-/-）对照。
缺乏 CD73 可能通过去抑制驻留的巨噬细胞和 T 细胞促进动脉粥样硬化的形成。Edn1 和 TG 水平的升高可能也有贡献。这确立了 CD73 衍生的腺苷是动脉粥样硬化的直接或间接调节因子。
