Grundmann Sebastian, Hoefer Imo, Ulusans Susann, van Royen Niels, Schirmer Stephan H, Ozaki C Keith, Bode Christoph, Piek Jan J, Buschmann Ivo
Department for Internal Medicine III (Cardiology and Angiology), University Hospital Freiburg, Freiburg, Germany.
Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1497-505. doi: 10.1152/ajpheart.00959.2004. Epub 2005 May 27.
The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established, little is known about its implications in the cardiovascular system. Because proliferation of arteriolar connections toward functional collateral arteries (arteriogenesis) is an inflammatory-like process, we tested in vivo the hypothesis that infliximab and etanercept have antiarteriogenic actions. Sixty-three New Zealand White rabbits underwent femoral artery occlusion and received infliximab, etanercept, or vehicle according to clinical dosage regimes. After 1 wk, collateral conductance, assessed with fluorescent microspheres, revealed significant inhibition of arteriogenesis (collateral conductance): 52.4 (SD 8.1), 35.2 (SD 7.7), and 33.3 (SD 10.1) ml x min(-1) x 100 mmHg(-1) with PBS, infliximab, and etanercept, respectively (P < 0.001). High-resolution angiography showed no significant differences in number of collateral arteries, but immunohistochemical analysis demonstrated a decrease in mean collateral diameter, proliferation of vascular smooth muscle cells, and reduction of leukocyte accumulation around collateral arteries in treated groups. Infliximab and etanercept bound to infiltrating leukocytes, which are important mediators of arteriogenesis. Infliximab induced monocyte apoptosis, and neither substance affected monocyte expression of the adhesion molecule Mac-1. We demonstrated that TNF-alpha serves as a pivotal modulator of arteriogenesis, which is attenuated by treatment with TNF-alpha inhibitors. Reduction of collateral conductance is most likely due to inhibition of perivascular leukocyte infiltration and subsequent lower vascular smooth muscle cell proliferation. This is the first report showing a negative influence of TNF-alpha inhibitors on collateral artery growth.
肿瘤坏死因子-α（TNF-α）的特异性拮抗剂英夫利昔单抗和依那西普，是治疗类风湿性关节炎和克罗恩病等炎症性疾病的常用药物。尽管TNF-α在慢性炎症性疾病中的重要性已得到充分证实，但对其在心血管系统中的影响却知之甚少。由于向功能性侧支动脉的小动脉连接增殖（动脉生成）是一个类似炎症的过程，我们在体内测试了英夫利昔单抗和依那西普具有抗动脉生成作用的假设。63只新西兰白兔接受股动脉闭塞，并根据临床剂量方案接受英夫利昔单抗、依那西普或赋形剂。1周后，用荧光微球评估的侧支传导显示动脉生成（侧支传导）受到显著抑制：用PBS、英夫利昔单抗和依那西普处理后，侧支传导分别为52.4（标准差8.1）、35.2（标准差7.7）和33.3（标准差10.1）ml·min-1·100 mmHg-1（P<0.001）。高分辨率血管造影显示侧支动脉数量无显著差异，但免疫组织化学分析表明，治疗组侧支动脉平均直径减小、血管平滑肌细胞增殖减少以及侧支动脉周围白细胞积聚减少。英夫利昔单抗和依那西普与浸润的白细胞结合，而浸润的白细胞是动脉生成的重要介质。英夫利昔单抗诱导单核细胞凋亡，两种药物均不影响单核细胞黏附分子Mac-1的表达。我们证明TNF-α是动脉生成的关键调节因子，TNF-α抑制剂治疗可减弱这种调节作用。侧支传导降低很可能是由于血管周围白细胞浸润受到抑制以及随后血管平滑肌细胞增殖减少所致。这是首份显示TNF-α抑制剂对侧支动脉生长有负面影响的报告。
