Abstract 14743: Intracellular Adenosine Suppresses Vsmc Phenotypic Switch Through Klf4 Gene Methylation
Background and objective: It is well known that adenosine affects the growth of vascular smooth muscle cells via adenosine receptors. Adenosine kinase (ADK) is an intracellular enzyme regulating the levels of adenosine in intracellular and further extracellular compartments. The effect of ADK on VSMC phenotypic switch is unknown. In this study, we evaluate phenotypic changes of VSCMs both in vitro and in vivo following deletion of ADK in VSMCs.
Methods and results: The expression of ADK in vascular wall was significant upregulated in mouse carotid artery ligation model. Heterogeneous deletion of ADK or specific ADK deletion in VSMCs led to remarkably decreased neointima in ligated mouse carotid arteries (Fig. A&B). This was accompanied with increased expression of VSMC differentiation markers and transcriptional factor KLF4 (Fig. D). In an in vitro setup, treatment of VSMCs with ADK shRNA or ADK inhibitors suppressed serum or PDGF-induced SMC proliferation and migration (Fig. C). This effect remained intact in the presence of adenosine receptor antagonists to A1, A2A, A2B and A3. Deletion of ADK in VSMCs increased the levels of intracellular adenosine, decreased the methylation levels of genes and histones, and augmented KLF4 expression. It is being investigated that upregulation of KLF4 was resulted from its gene hypomethylation in response to elevated intracellular adenosine following ADK deletion/knockdown or inhibition.
Conclusions: Our data demonstrate that ADK deletion/inhibition suppresses neointima formation in injured arteries through a novel epigenetic pathway but not classic adenosine receptors, and ADK is a promising therapeutic target in the treatment of arterial diseases such as atherosclerosis and arterial neointima formation following arterial angioplasty.
Author Disclosures: Y. Wang: None. Y. Xu: None. X. Zeng: None. Y. Zhou: None. Z. Liu: None. C. Wu: None. Q. Li: None. Y. Huo: None.
- © 2015 by American Heart Association, Inc.