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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment
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Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment

机译：可溶性鸟苷酸环化酶的抗炎活性：依赖cGMP的P选择素表达下调和白细胞募集

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摘要

Nitric oxide (NO) production by the vascular endothelium maintains an essential antiinflammatory, cytoprotective influence on the blood vessel wall. A key component of this activity is attributed to prevention of leukocyte-endothelial cell interactions, yet the underlying mechanisms remain unclear. The NO receptor, soluble guanylate cyclase (sGC), is expressed in endothelial cells but fulfils an unknown function. Therefore, we used intravita! microscopy in mesenteric postcapillary venules from WT and endothelial nitric oxide synthase (eNOS) knockout (eNOS~(-/-)) mice, and an sGC activator (BAY 41-2272), to investigate a potential role for sGC in the regulation of adhesion molecule expression and leukocyte recruitment. Leukocyte rolling and adhesion was 6-fold greater in eNOS~(-/-) than WT animals. BAY 41-2272 and the NO-donor, dieth-ylamine-NONOate, reduced leukocyte rolling and adhesion in eNOS~(-/-) mice to levels observed in WT animals. These effects were blocked by the sGC inhibitor ODQ [1H-(1,2,4)oxadiazolo(4,3-a)qui-noxalin-1-one], which itself caused a 6-fold increase in leukocyte rolling and adhesion in WT mice. Increased leukocyte rolling and adhesion in IL-1β-treated mice was also inhibited by BAY 41-2272. Fluorescence-activated cell sorting analysis in vitro and a specific P-selectin neutralizing antibody in vivo revealed that selective down-regulation of P-selectin expression accounted for the anti-adhesive effects of sGC activation. These data demonstrate that sGC plays a key antiinflammatory role by inhibiting P-selectin expression and leukocyte recruitment.
机译：血管内皮产生的一氧化氮（NO）对血管壁保持了必不可少的抗炎，细胞保护作用。该活性的关键成分归因于预防白细胞-内皮细胞相互作用，但其潜在机制仍不清楚。 NO受体，可溶性鸟苷酸环化酶（sGC），在内皮细胞中表达，但功能未知。因此，我们使用了intravita！显微镜观察野生型和肠内一氧化氮合酶（eNOS）（eNOS〜（-/-））小鼠肠系膜后小静脉和sGC激活剂（BAY 41-2272）的作用，以研究sGC在调节粘着性中的潜在作用分子表达和白细胞募集。 eNOS〜（-/-）中白细胞滚动和粘连比野生动物大6倍。 BAY 41-2272和NO-供体，二乙胺-NONOate，将eNOS〜（-/-）小鼠中的白细胞滚动和粘附降低至野生动物中观察到的水平。这些作用被sGC抑制剂ODQ [1H-（1,2,4）恶二唑（4,3-a）qui-noxalin-1-one]阻断，后者本身引起白细胞滚动和粘附增加6倍。 WT小鼠。 BAY 41-2272也抑制了IL-1β治疗的小鼠中白细胞滚动和粘附的增加。体外荧光激活细胞分选分析和体内特异性P-选择蛋白中和抗体显示，P-选择蛋白表达的选择性下调解释了sGC激活的抗黏附作用。这些数据表明，sGC通过抑制P-选择蛋白表达和白细胞募集发挥关键的抗炎作用。

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