Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Circ Res. 2011 Oct 28;109(10):1132-40. doi: 10.1161/CIRCRESAHA.111.254573. Epub 2011 Sep 22.
Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fcγ receptor IIB (FcγRIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization.
How CRP activates FcγRIIB in endothelium is not known. We determined the role of Fcγ receptor I (FcγRI) and the basis for coupling of FcγRI to FcγRIIB in endothelium.
In cultured endothelial cells, FcγRI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via FcγRI. CRP-induced increases in FcγRIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5'-phosphatase 1 activation were Src-dependent, and Src inhibition prevented eNOS antagonism by CRP. Similar processes mediated eNOS antagonism by aggregated IgG used to mimic immune complex. Carotid artery re-endothelialization was evaluated in offspring from crosses of CRP transgenic mice (TG-CRP) with either mice lacking the γ subunit of FcγRI (FcRγ(-/-)) or FcγRIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcRγ(-/-); TG-CRP and FcγRIIB(-/-); TG-CRP mice.
CRP antagonism of eNOS is mediated by the coupling of FcγRI to FcγRIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both FcγRI and FcγRIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. FcγRI and FcγRIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.
C 反应蛋白（CRP）升高与心血管疾病风险增加和内皮功能障碍有关。CRP 通过 IgG 受体 Fcγ 受体 IIB（FcγRIIB）、其免疫受体酪氨酸抑制基序和含 SH2 结构域的肌醇 5'-磷酸酶 1 的过程来拮抗内皮型一氧化氮合酶（eNOS）。在小鼠中，CRP 对 eNOS 的作用使颈动脉再内皮化减弱。
CRP 如何在内皮细胞中激活 FcγRIIB 尚不清楚。我们确定了 Fcγ 受体 I（FcγRI）的作用以及 FcγRI 与内皮细胞中 FcγRIIB 偶联的基础。
在培养的内皮细胞中，FcγRI 阻断抗体可防止 CRP 拮抗 eNOS，CRP 通过 FcγRI 激活Src。CRP 诱导的 FcγRIIB 免疫受体酪氨酸抑制基序磷酸化和含 SH2 结构域的肌醇 5'-磷酸酶 1 激活均依赖于Src，Src 抑制可防止 CRP 拮抗 eNOS。类似的过程介导了用于模拟免疫复合物的聚集 IgG 对 eNOS 的拮抗作用。CRP 转基因小鼠（TG-CRP）与缺乏 FcγRI γ 亚基（FcRγ（-/-））或 FcγRIIB（-/-）小鼠杂交后代的颈动脉再内皮化情况进行了评估。与野生型相比，TG-CRP 中的再内皮化受损，但 FcRγ（-/-）；TG-CRP 和 FcγRIIB（-/-）；TG-CRP 小鼠均正常。
CRP 通过 Src 激酶将 FcγRI 与 FcγRIIB 偶联，从而拮抗 eNOS，导致含 SH2 结构域的肌醇 5'-磷酸酶 1 激活，该机制一致，FcγRI 和 FcγRIIB 均为 CRP 在体内阻断内皮修复所必需。类似的机制是免疫复合物拮抗 eNOS 的基础。FcγRI 和 FcγRIIB 可能是预防炎症或免疫复合物介导的条件下内皮功能障碍的新型治疗靶点。
