Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation
Adenosine kinase is critical for neointima formation after vascular injury by inducing aberrant DNA hypermethylation
复制标题
腺苷激酶通过诱导异常 DNA 高甲基化对血管损伤后新内膜形成至关重要
DOI：
10.1093/cvr/cvaa040
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发表时间：
2021-02-01
影响因子：
10.8
通讯作者：
Huo, Yuqing
中科院分区：
文献类型：
--
作者：
Wang, Yong;Xu, Yiming;Huo, Yuqing
腺苷受体和细胞外腺苷已被证明可调节血管平滑肌细胞（VSMC）增殖和新生内膜形成。腺苷激酶（adenosinekinase，ADK）是调节细胞内腺苷水平的主要酶，但其在VSMC中的功能尚不清楚.在这里，我们研究了ADK在血管损伤诱导的平滑肌增殖的作用，并描绘了其作用的机制。方法和结果我们发现，ADK的表达较高的损伤血管的新生内膜和血小板源性生长因子处理的VSMCs。ADK的遗传和药理学抑制足以减弱由于抑制VSMC增殖而引起的动脉损伤诱导的新生内膜形成。在机制上，我们使用infinium甲基化分析和bisutfite测序，我们发现ADK代谢细胞内腺苷并加强转甲基化途径，然后诱导异常的DNA超甲基化。药物抑制异常DNA甲基化增加KLF4表达，抑制VSMC增殖以及新生内膜形成。在人股动脉中，我们观察到ADK表达增加，DNA超甲基化以及狭窄血管新生内膜VSMC中KLF4表达减少，这表明我们在小鼠中的发现与人类疾病相关，并且可能具有翻译意义。从而下调KLF4表达并促进新生内膜形成。这些发现推进了靶向ADK作为表观遗传调节剂对抗血管损伤的可能性。[图形]。
Aims Adenosine receptors and extracellular adenosine have been demonstrated to modulate vascular smooth muscle cell (VSMC) proliferation and neointima formation. Adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels but is function in VSMC remains unclear. Here, we investigated the role of ADK in vascular injury-induced smooth muscle proliferation and delineated the mechanisms underlying its action.Methods and results We found that ADK expression was higher in the neointima of injured vessels and in platelet-derived growth factor-treated VSMCs. Genetic and pharmacological inhibition of ADK was enough to attenuate arterial injury-induced neointima formation due to inhibition of VSMC proliferation. Mechanistically, using infinium methylation assays and bisutfite sequencing, we showed that ADK metabolized the intracellular adenosine and potentiated the transmethylation pathway, then induced the aberrant DNA hypermethylation. Pharmacological inhibition of aberrant DNA hypermethylation increased KLF4 expression and suppressed VSMC proliferation as well as the neointima formation. Importantly, in human femoral arteries, we observed increased ADK expression and DNA hypermethylation as well as decreased KLF4 expression in neointimat VSMCs of stenotic vessels suggesting that our findings in mice are relevant for human disease and may hold translational significance.Conclusion Our study unravels a novel mechanism by which ADK promotes VSMC proliferation via inducing aberrant DNA hypermethylation, thereby down-regulating KLF4 expression and promoting neointima formation. These findings advance the possibility of targeting ADK as an epigenetic modulator to combat vascular injury.[GRAPHICS].