Inhibition of lysine-specific demethylase 1A suppresses neointimal hyperplasia by targeting bone morphogenetic protein 2 and mediating vascular smooth muscle cell phenotype
Inhibition of lysine-specific demethylase 1A suppresses neointimal hyperplasia by targeting bone morphogenetic protein 2 and mediating vascular smooth muscle cell phenotype
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抑制赖氨酸特异性去甲基化酶 1A 通过靶向骨形态发生蛋白 2 并介导血管平滑肌细胞表型来抑制新生内膜增生
DOI：
10.1111/cpr.12711
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发表时间：
2020
影响因子：
8.5
通讯作者：
Yang Haifeng
中科院分区：
文献类型：
--
作者：
Zhang Xiaobo;Huang Tao;Zhai Heng;Peng Wenpeng;Zhou Yong;Li Qi;Yang Haifeng
血管疾病与血管平滑肌细胞(VSMCs)表型转换有关。我们研究了骨形态发生蛋白(BMP)-2在控制VSMC表型和血管病变进展中的作用。赖氨酸(K)特异性去甲基酶1A(KDM1A)被鉴定为靶向BMP-2的酶，并被用作调节VSMC BMP-2表达的治疗手段。材料和方法血管紧张素II刺激VSMC，检测KDM1A和BMP-2的表达。检测VSMC的增殖、凋亡和表型。建立在体主动脉损伤模型，通过关键标志物的表达评价VSMC的行为。结果证实了KDM1A对BMP-2活性的抑制作用，并证实了KDM1A抑制VSMC从收缩表型向合成表型转化的作用。在血管紧张素II处理的VSMCs中，KDM1A抑制引起细胞增殖和炎症反应的减少。在体内，KDM1A抑制减轻了术后新生内膜形成和胶原沉积，阻止了VSMCs转变为合成表型，并抑制了疾病的发生。这些过程是由BMP-2通过典型的小母体对抗截瘫信号介导的，该信号与BMP受体1A和1B的激活有关。结论KDM1A和BMP-2之间的调控相关性为血管重塑和VSMC表型调控提供了新的思路。报道的发现有助于开发针对血管疾病的创新策略。
ObjectivesVascular disorders are associated with phenotypical switching of vascular smooth muscle cells (VSMCs). We investigated the effect of bone morphogenetic protein (BMP)‐2 in controlling VSMC phenotype and vascular disorder progression. Lysine (K)‐specific demethylase 1A (KDM1A) has been identified to target BMP‐2 and is employed as a therapeutic means of regulating BMP‐2 expression in VSMCs.Materials and methodsVSMCs were stimulated with angiotensin II, and the expression of KDM1A and BMP‐2 was detected. VSMC proliferation, apoptosis, and phenotype were evaluated. An in vivo aortic injury model was established, and VSMC behaviour was evaluated by the expression of key markers. The activation of BMP‐2–associated signalling pathways was examined.ResultsWe confirmed the inhibitory effect of KDM1A on BMP‐2 activity and demonstrated that KDM1A inhibition prevented VSMC transformation from a contractile to synthetic phenotype. In angiotensin II‐treated VSMCs, KDM1A inhibition triggered a decrease in cell proliferation and inflammatory response. In vivo, KDM1A inhibition alleviated post‐surgery neointimal formation and collagen deposition, preventing VSMCs from switching into a synthetic phenotype and suppressing disease onset. These processes were mediated by BMP‐2 through canonical small mothers against decapentaplegic signalling, which was associated with the activation of BMP receptors 1A and 1B.ConclusionsThe regulatory correlation between KDM1A and BMP‐2 offers insights into vascular remodelling and VSMC phenotypic modulation. The reported findings contribute to the development of innovative strategies against vascular disorders.