Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling
Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling
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DOI：
10.1152/ajpheart.00641.2013
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发表时间：
2014-03-01
影响因子：
4.8
通讯作者：
Vazquez-Padron, Roberto I.
中科院分区：
文献类型：
--
作者：
Rodriguez-Menocal, Luis;Faridi, Mohd Hafeez;Vazquez-Padron, Roberto I.
衰老与病理性血管重塑和新内膜增生增加有关。了解衰老如何加剧这一过程对于预防老年人心血管并发症至关重要。这项研究提出了衰老维持白细胞粘附、血管炎症和损伤后新生内膜厚度增加的机制。使用微阵列分析、免疫组织化学和 LINCOplex 测定在大鼠球囊损伤模型中评估衰老对血管重塑的影响。与年轻动物相比，衰老大鼠的受损动脉会形成更厚的新内膜，这与组织巨噬细胞数量增加和血管 IL-18 增加显着相关。事实上，与年轻大鼠相比，老年动物受损脉管系统中的 IL-18 含量高出 23 倍，而两组动物的循环水平相似。使用氯膦酸盐脂质体消除老年大鼠的巨噬细胞可改善 IL-18 的血管积累，并显着减少新内膜的形成。研究发现 IL-18 可以抑制血管平滑肌细胞 (VSMC) 和巨噬细胞的凋亡，从而有利于新内膜的形成和炎症。此外，老年大鼠受损动脉中积累的纤维蛋白原-γ是年轻动物的 18 倍。将大鼠腹腔巨噬细胞与固定化 IL-18 一起孵育可增加白细胞对纤维蛋白原的粘附，并表明巨噬细胞、VSMC 和新内膜增生期间纤维蛋白原沉积之间存在促炎性正反馈回路。总之，我们的数据表明，衰老大鼠损伤后血管细胞因子和纤维蛋白原的浓度变化有助于局部炎症和损伤后新内膜的形成。
Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC)and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-gamma than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation.