Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment
Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment
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DOI：
10.1073/pnas.0304264101
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发表时间：
2004-02-03
影响因子：
11.1
通讯作者：
Hobbs, AJ
中科院分区：
文献类型：
--
作者：
Ahluwalia, A;Foster, P;Hobbs, AJ
血管内皮细胞产生的一氧化氮（NO）对血管壁具有重要的细胞保护作用。这种活性的一个关键组成部分是由于防止白细胞-内皮细胞相互作用，但潜在的机制仍不清楚。NO受体，可溶性鸟苷酸环化酶（sGC），在内皮细胞中表达，但履行一个未知的功能。因此，我们在WT和内皮型一氧化氮合酶（eNOS）敲除（eNOS（-/-））小鼠的肠系膜毛细血管后小静脉中使用活体显微镜，并使用sGC激活剂（BAY 41-2272），以研究sGC在调节粘附分子表达和白细胞募集中的潜在作用。eNOS（-/-）中的白细胞滚动和粘附是WT动物的6倍。BAY 41-2272和NO-供体，二乙胺-NONOate，减少eNOS（-/-）小鼠中的白细胞滚动和粘附至WT动物中观察到的水平。这些作用被sGC抑制剂ODQ [1H-（1，2，4）恶二唑并（4，3-a）喹喔啉-1-酮]阻断，其本身导致WT小鼠中白细胞滚动和粘附增加6倍。BAY 41-2272还可抑制IL-1 β处理小鼠中白细胞滚动和粘附增加。体外粘附激活细胞分选分析和体内特异性P-选择素中和抗体显示，选择性下调P-选择素表达是sGC激活的抗粘附作用的原因。这些数据表明，sGC通过抑制P-选择素表达和白细胞募集发挥关键的抗炎作用。
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 intravital 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, diethylamine-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)quinoxalin-1-one], which itself caused a 6-fold increase in leukocyte rolling and adhesion in WT mice. Increased leukocyte rolling and adhesion in IL-1beta-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 anti inflammatory role by inhibiting P-selectin expression and leukocyte recruitment.