Axl modulates immune activation of smooth muscle cells in vein graft remodeling
Axl modulates immune activation of smooth muscle cells in vein graft remodeling
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DOI：
10.1152/ajpheart.00495.2015
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发表时间：
2015-09-15
影响因子：
4.8
通讯作者：
Korshunov, Vyacheslav A.
中科院分区：
文献类型：
--
作者：
Batchu, Sri N.;Xia, Jixiang;Korshunov, Vyacheslav A.
平滑肌细胞免疫激活的病理生理机制还不清楚。最近在冠状动脉旁路移植术后患者的动脉中发现了受体酪氨酸激酶Axl的表达增加。在本研究中，我们假设Axl依赖的平滑肌细胞免疫激活调节静脉移植物重塑。我们观察到血管和全身Axl耗竭后，静脉移植物内膜增厚减少了两倍。Axl的局部缺失对免疫激活的影响最大，而Axl的全身缺失由于静脉移植物中细胞凋亡的增加而减少了内膜。从Axl敲除小鼠分离的原代平滑肌细胞通过阻止STAT 1通路而具有降低的促炎反应。Axl的缺乏增加了平滑肌细胞中细胞因子信号传导抑制因子（SOCS）1的表达，SOCS 1是STAT 1的主要抑制蛋白。超声成像表明Axl的血管耗竭降低了静脉移植物硬度。Axl表达决定了移植静脉内膜中STAT 1-SOCS 1的平衡和重塑的进展。本研究的结果表明，Axl通过抑制静脉移植物重塑中活化的平滑肌细胞中的SOCS 1来促进STAT 1信号传导。
The pathophysiological mechanisms of the immune activation of smooth muscle cells are not well understood. Increased expression of Axl, a receptor tyrosine kinase, was recently found in arteries from patients after coronary bypass grafts. In the present study, we hypothesized that Axl-dependent immune activation of smooth muscle cells regulates vein graft remodeling. We observed a twofold decrease in intimal thickening after vascular and systemic depletion of Axl in vein grafts. Local depletion of Axl had the greatest effect on immune activation, whereas systemic deletion of Axl reduced intima due to an increase in apoptosis in vein grafts. Primary smooth muscle cells isolated from Axl knockout mice had reduced proinflammatory responses by prevention of the STAT1 pathway. The absence of Axl increased suppressor of cytokine signaling (SOCS) 1 expression in smooth muscle cells, a major inhibitory protein for STAT1. Ultrasound imaging suggested that vascular depletion of Axl reduced vein graft stiffness. Axl expression determined the STAT1-SOCS1 balance in vein graft intima and progression of the remodeling. The results of this investigation demonstrate that Axl promotes STAT1 signaling via inhibition of SOCS1 in activated smooth muscle cells in vein graft remodeling.