Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, W12 ONN, United Kingdom;
J Immunol. 2014 May 1;192(9):4316-27. doi: 10.4049/jimmunol.1301702. Epub 2014 Mar 26.
Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.
内皮损伤和功能障碍先于同种异体移植血管病和系统性自身免疫性疾病中的加速动脉疾病，并涉及致病性抗体和补体。最近的报告表明，从钙调神经磷酸酶抑制剂转换为雷帕霉素可降低移植后血管病，并延长心脏移植后的存活期。这些患者中的大多数还接受他汀类药物治疗。我们研究了雷帕霉素和阿托伐他汀在人内皮细胞中潜在的保护作用机制，并确定了两者之间的协同作用。从机制上讲，阿托伐他汀和雷帕霉素激活了蛋白激酶 Cα、AMP 激活的蛋白激酶和 CREB 依赖性血管保护途径，该途径通过与 cAMP 反应元件结合诱导衰变加速因子（DAF）启动子活性，突变该元件可减弱启动子活性。这种反应显著增加了内皮细胞表面的 DAF，增强了对补体介导损伤的保护作用。辛伐他汀可再现与雷帕霉素的协同作用，而用环孢素或霉酚酸酯代替雷帕霉素与阿托伐他汀联合则无效。重要的是，这种协同作用在体内得到了再现，只有阿托伐他汀和雷帕霉素联合治疗才能诱导小鼠主动脉内皮细胞上的 DAF。我们认为，这种途径代表了一种重要的治疗性诱导血管保护机制，可用于致病性抗体和补体介导的疾病，包括移植后血管病和系统性红斑狼疮。虽然我们的研究重点是血管内皮细胞，但鉴于 DAF 的广泛细胞表达，这些发现可能具有广泛的适用性。
