Implication for transglutaminase 2-mediated activation of β-catenin signaling in neointimal vascular smooth muscle cells in chronic cardiac allograft rejection.
Implication for transglutaminase 2-mediated activation of β-catenin signaling in neointimal vascular smooth muscle cells in chronic cardiac allograft rejection.
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DOI：
10.1016/j.healun.2012.04.009
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Nurminskaya M
中科院分区：
文献类型：
--
作者：
Beazley KE;Zhang T;Lima F;Pozharskaya T;Niger C;Tzitzikov E;Azimzadeh AM;Nurminskaya M
同种异体心脏移植血管病变（CAV）仍然是长期移植排斥反应的主要原因。其特点是血管平滑肌细胞（VSMCs）过度增生。典型β-catenin信号是VSMC发育过程中增殖的重要调控因子；然而，这一途径及其调控在CAV进展中的作用尚不清楚。我们研究了β-catenin信号的活性以及一种假定的激活配体，转谷氨酰胺酶2 （TG2）在慢性心脏排斥反应中的作用。将Bm12小鼠的心脏移植到C57BL/6小鼠（II类错配）体内，移植8周后收获同种异体移植物。我们分析了β-catenin蛋白的积累和亚细胞分布以及β-catenin信号传导的几个组分的表达，作为途径激活的标志。在体外，PDGF处理用于模拟VSMC和器官型心脏切片培养中的炎症环境。β-catenin靶基因的表达增强，以及β-catenin蛋白在异体移植血管闭塞的VSMCs内的积累和核定位，证明了β-catenin在异体移植血管中比在等移植物或naïve心脏中激活。在同种异体移植物中，VSMCs中β-catenin信号激活剂TG2的表达显著增加。此外，我们的离体数据表明，TG2是心脏组织中VSMC增殖和PDGF激活β-catenin所必需的。β-连环蛋白信号在小鼠同种异体心脏移植闭塞血管中被激活。TG2是该信号通路的内源性激活因子，因此可能在慢性同种异体移植排斥过程中CAV的发病机制中发挥作用。
Cardiac allograft vasculopathy (CAV) remains the main cause of long-term transplant rejection. It is characterized by hyperproliferation of vascular smooth muscle cells (VSMCs). Canonical β-catenin signaling is a critical regulator of VSMC proliferation in development; however, the role of this pathway and its regulation in CAV progression are obscure. We investigated the activity of β-catenin signaling and the role for a putative activating ligand, transglutaminase 2 (TG2), in chronic cardiac rejection. Hearts from Bm12 mice were transplanted into C57BL/6 mice (Class II mismatch), and allografts were harvested 8 weeks after transplantation. Accumulation and sub-cellular distribution of β-catenin protein and expression of several components of β-catenin signaling were analyzed as hallmarks of pathway activation. In vitro, PDGF treatment was used to mimic the inflammatory milieu in VSMC and organotypic heart slice cultures. Activation of β-catenin in allografts compared to isografts or naïve hearts was evidenced by the augmented expression of β-catenin target genes, as well as the accumulation and nuclear localization of the β-catenin protein in VSMCs of the occluded allograft vessels. Expression of TG2, an activator of β-catenin signaling in VSMCs, was dramatically increased in allografts. Further, our ex vivo data demonstrate that TG2 is required for VSMC proliferation and for β-catenin activation by PDGF in cardiac tissue. β-catenin signaling is activated in occluded vessels in murine cardiac allografts. TG2 is implicated as an endogenous activator of this signaling pathway and may therefore have a role in the pathogenesis of CAV during chronic allograft rejection.
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影响因子：
4.8
作者：
Abid, MR;Yano, K;Aird, WC
通讯作者：
Aird, WC
影响因子：
1.8
作者：
Cho, Byung-Ryul;Kim, Min-Kyung;Kim, Dae-Joong
通讯作者：
Kim, Dae-Joong
影响因子：
0.9
作者：
Lemstrom, K;Sihvola, R;Koskinen, P
通讯作者：
Koskinen, P
影响因子：
64.5
作者：
Inoki, Ken;Ouyang, Hongjiao;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
影响因子：
--
作者：
Autieri, MV
通讯作者：
Autieri, MV