Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Japan.
Peptides. 2010 May;31(5):865-71. doi: 10.1016/j.peptides.2010.01.011. Epub 2010 Feb 2.
Donor organ damage caused by cold preservation is a major problem affecting liver transplantation. Cold preservation most easily damages liver sinusoidal endothelial cells (LSECs), and information about the molecules modulating LSECs function can provide the basis for new therapeutic strategies. Adrenomedullin (AM) is a peptide known to possess anti-apoptotic and anti-inflammatory properties. AM is abundant in vascular endothelial cells, but levels are comparatively low in liver, and little is known about its function there. In this study, we demonstrated both AM and its receptors are expressed in LSECs. AM treatment reduced LSECs loss and apoptosis under cold treatment. AM also downregulated cold-induced expression of TNFalpha, IL1beta, IL6, ICAM1 and VCAM1. AM reduced apoptosis and expression of ICAM1 and VCAM1 in an in vivo liver model subjected to cold storage. Conversely, apoptosis was exacerbated in livers from AM and RAMP2 (AM receptor activity-modifying protein) knockout mice. These results suggest that AM expressed in LSECs exerts a protective effect against cold-organ damage through modulation of apoptosis and inflammation.
供体器官在冷保存过程中受到的损伤是影响肝移植的一个主要问题。冷保存最容易损伤肝窦内皮细胞（LSECs），而关于调节 LSECs 功能的分子信息可以为新的治疗策略提供基础。肾上腺髓质素 (AM) 是一种具有抗凋亡和抗炎特性的肽。AM 在血管内皮细胞中含量丰富，但在肝脏中的含量相对较低，其在肝脏中的功能知之甚少。在这项研究中，我们证明 AM 及其受体均在 LSECs 中表达。AM 处理可减少冷处理下 LSECs 的丢失和凋亡。AM 还可下调冷诱导的 TNFalpha、IL1beta、IL6、ICAM1 和 VCAM1 的表达。AM 可减少体内冷储存肝脏模型中的细胞凋亡和 ICAM1 和 VCAM1 的表达。相反，AM 和 RAMP2（AM 受体活性修饰蛋白）敲除小鼠的肝脏中的细胞凋亡加剧。这些结果表明，LSECs 中表达的 AM 通过调节细胞凋亡和炎症对冷器官损伤发挥保护作用。
