Abstract

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 bisulfite 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 neointimal 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.

中文翻译：

---

腺苷激酶通过诱导异常的 DNA 高甲基化对血管损伤后的新内膜形成至关重要。

摘要

宗旨

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) 增殖和新内膜形成。腺苷激酶 (ADK) 是调节细胞内腺苷水平的主要酶，但在 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中的作用，并描述了其作用的潜在机制。

方法和结果

我们发现 ADK 在受损血管的新内膜和血小板衍生生长因子处理的 VSMC 中表达较高。由于抑制 VSMC 增殖，ADK 的遗传和药理学抑制足以减弱动脉损伤诱导的新内膜形成。从机制上讲，使用 infinium 甲基化测定和亚硫酸氢盐测序，我们发现 ADK 代谢细胞内腺苷并增强转甲基化途径，然后诱导异常的 DNA 高甲基化。对异常 DNA 高甲基化的药理学抑制增加了 KLF4 表达并抑制了 VSMC 增殖以及新内膜的形成。重要的是，在人类股动脉中，

结论

我们的研究揭示了 ADK 通过诱导异常 DNA 高甲基化促进 VSMC 增殖的新机制，从而下调 KLF4 表达并促进新内膜形成。这些发现提高了靶向 ADK 作为表观遗传调节剂以对抗血管损伤的可能性。