TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.
复制标题
TET2对移植血管病变中血管平滑肌细胞凋亡和内膜增厚的保护作用
DOI：
10.1161/circulationaha.120.050553
复制
发表时间：
2021-08-10
期刊：
影响因子：
37.8
通讯作者：
Martin KA
中科院分区：
文献类型：
--
作者：
Ostriker AC;Xie Y;Chakraborty R;Sizer AJ;Bai Y;Ding M;Song WL;Huttner A;Hwa J;Martin KA
冠状动脉移植物血管病变（CAV）是心脏移植后的一种严重后遗症，其主要表现为动脉内膜增厚，限制了冠状动脉血流。目前还没有靶向治疗来预防或减少这种导致移植失败的病理。血管平滑肌细胞（VSMC）表型可塑性在CAV新生内膜形成中至关重要。泰特甲基胞嘧啶双加氧酶2（TET 2）是VSMC表型的重要表观遗传调节因子，但TET 2在CAV进展中的作用尚不清楚。我们评估了TET 2在人CAV和肾移植样品中的表达和活性。我们还在野生型和诱导型平滑肌特异性Tet 2基因敲除小鼠中采用了移植物动脉病（GA）的性别不匹配的小鼠主动脉移植物模型;并在小鼠和人VSMC中使用敲低、过表达和转录组学方法进行了体外研究，以评估TET 2在VSMC对IFNу反应中的作用，IFN у是一种由T细胞产生的细胞因子，可驱动CAV进展。在本研究中，我们发现TET 2的表达和活性在人CAV和肾移植样品中以及在GA的鼠主动脉移植物模型中负调控。在体外，IFN-у足以抑制TET 2并诱导VSMC活化。TET 2耗竭模拟了IFNу的作用，TET 2过表达挽救了IFNу诱导的去分化。在主动脉移植物和股动脉再狭窄模型中，VSMC特异性TET 2耗竭导致VSMC凋亡增加和中膜变薄。在GA中，这种凋亡与增殖密切相关。在体外，TET 2缺陷的VSMC更容易响应于IFNγ而发生凋亡，并表达对外源性凋亡信号的敏感性增加的特征。值得注意的是，用高剂量抗坏血酸增强TET 2酶活性以TET 2依赖的方式挽救了GA诱导的VSMC凋亡和内膜增厚的效果。TET 2在CAV和GA中被抑制，可能由IFNу介导。TET 2在移植血管病变或IFN-γ刺激的情况下保护VSMC免于凋亡。全身性抗坏血酸促进体内TET 2活性可减少VSMC凋亡和内膜增厚。这些数据表明，促进CAV中TET 2活性可能是限制CAV进展的有效策略。
Coronary allograft vasculopathy (CAV) is a devastating sequelae of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET methylcytosine dioxygenase 2 (TET2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. We assessed TET2 expression and activity in human CAV and renal transplant samples. We also employed the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild type and inducible smooth muscle-specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNу, a cytokine elaborated by T cells that drives CAV progression. In the present study, we found that TET2 expression and activity is negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNу was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNу, and TET2 overexpression rescued IFNу-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2 deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Notably, enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. TET2 is repressed in CAV and GA, likely mediated by IFNу. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNу stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.