Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation.
Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation.
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DOI：
10.1038/s44161-022-00175-w
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发表时间：
2022-12
期刊：
影响因子：
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通讯作者：
Kessler, Thorsten
中科院分区：
文献类型：
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作者：
Mauersberger, Carina;Sager, Hendrik B;Wobst, Jana;Dang, Tan An;Lambrecht, Laura;Koplev, Simon;Stroth, Marlene;Bettaga, Noomen;Schlossmann, Jens;Wunder, Frank;Friebe, Andreas;Bjorkegren, Johan L M;Dietz, Lisa;Maas, Sanne L;van der Vorst, Emiel P C;Sandner, Peter;Soehnlein, Oliver;Schunkert, Heribert;Kessler, Thorsten
血小板中编码可溶性鸟苷酸环化酶 (sGC) 的基因变异与冠状动脉疾病 (CAD) 风险相关。在这里，通过使用组织学、流式细胞术和活体显微镜，我们表明，易发生动脉粥样硬化的 Ldlr−/− 小鼠血小板中 sGC 的功能丧失有助于动脉粥样硬化斑块的形成，特别是通过增加体内白细胞对动脉粥样硬化病变的粘附。体外实验表明，缺乏 sGC 的活化血小板上清液通过激活内皮细胞 (EC) 来促进白细胞与内皮细胞 (EC) 的粘附。血小板释放细胞因子的分析表明，sGC 耗尽的血小板减少了血小板血管生成素-1 的释放，这在来自 GUCY1A1 风险等位基因携带者的分离人血小板中得到了验证，增强了白细胞对 EC 的粘附。重要的是，在易发生动脉粥样硬化的 Ldlr-/- 小鼠中，药理学 sGC 刺激在体外增加了血小板血管生成素-1 的释放，并减少了白细胞的募集和动脉粥样硬化斑块的形成。因此，药理 sGC 刺激可能代表了预防和治疗 CAD 的潜在治疗策略。
Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. I mp or ta ntly, p ha rm ac ol ogical sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.