Wong Cindy W, Christen Thomas, Roth Isabelle, Chadjichristos Christos E, Derouette Jean-Paul, Foglia Bernard F, Chanson Marc, Goodenough Daniel A, Kwak Brenda R
Division of Cardiology, Department of Internal Medicine, Geneva University Hospitals, CH-1211 Geneva, Switzerland.
Nat Med. 2006 Aug;12(8):950-4. doi: 10.1038/nm1441. Epub 2006 Jul 23.
A genetic polymorphism in the human gene encoding connexin37 (CX37, encoded by GJA4, also known as CX37) has been reported as a potential prognostic marker for atherosclerosis. The expression of this gap-junction protein is altered in mouse and human atherosclerotic lesions: it disappears from the endothelium of advanced plaques but is detected in macrophages recruited to the lesions. The role of CX37 in atherogenesis, however, remains unknown. Here we have investigated the effect of deleting the mouse connexin37 (Cx37) gene (Gja4, also known as Cx37) on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, an animal model of this disease. We find that Gja4(-/-)Apoe(-/-) mice develop more aortic lesions than Gja4(+/+)Apoe(-/-) mice that express Cx37. Using in vivo adoptive transfer, we show that monocyte and macrophage recruitment is enhanced by eliminating expression of Cx37 in these leukocytes but not by eliminating its expression in the endothelium. We further show that Cx37 hemichannel activity in primary monocytes, macrophages and a macrophage cell line (H36.12j) inhibits leukocyte adhesion. This antiadhesive effect is mediated by release of ATP into the extracellular space. Thus, Cx37 hemichannels may control initiation of the development of atherosclerotic plaques by regulating monocyte adhesion. H36.12j macrophages expressing either of the two CX37 proteins encoded by a polymorphism in the human GJA4 gene show differential ATP-dependent adhesion. These results provide a potential mechanism by which a polymorphism in CX37 protects against atherosclerosis.
据报道，人类编码连接蛋白37（CX37，由GJA4编码，也称为CX37）的基因中的一种遗传多态性是动脉粥样硬化的潜在预后标志物。这种间隙连接蛋白的表达在小鼠和人类动脉粥样硬化病变中发生改变：它在晚期斑块的内皮中消失，但在募集到病变部位的巨噬细胞中被检测到。然而，CX37在动脉粥样硬化发生中的作用仍然未知。在这里，我们研究了删除小鼠连接蛋白37（Cx37）基因（Gja4，也称为Cx37）对载脂蛋白E缺陷（Apoe(-/-)）小鼠动脉粥样硬化的影响，该小鼠是这种疾病的动物模型。我们发现，与表达Cx37的Gja4(+/+)Apoe(-/-)小鼠相比，Gja4(-/-)Apoe(-/-)小鼠出现更多的主动脉病变。通过体内过继转移，我们表明，消除这些白细胞中Cx37的表达可增强单核细胞和巨噬细胞的募集，但消除其在内皮中的表达则不会。我们进一步表明，原代单核细胞、巨噬细胞和巨噬细胞系（H36.12j）中的Cx37半通道活性可抑制白细胞粘附。这种抗粘附作用是由ATP释放到细胞外空间介导的。因此，Cx37半通道可能通过调节单核细胞粘附来控制动脉粥样硬化斑块形成的起始。表达人类GJA4基因多态性编码的两种CX37蛋白之一的H36.12j巨噬细胞表现出不同的ATP依赖性粘附。这些结果提供了一种潜在机制，通过该机制CX37中的多态性可预防动脉粥样硬化。
