Yong Wang1,2, Yiming Xu2,3, Siyuan Yan4, Kaixiang Cao3, Xianqiu Zeng5, Yaqi Zhou5, Zhiping Liu2,5, Qiuhua Yang2,5, Yue Pan6, Xiaoling Wang6, Detlev Boison7, Yunchao Su8, Xuejun Jiang4, Vijay S Patel9, David Fulton2, Neal L Weintraub2, Yuqing Huo2. 1. College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China. 2. Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. 3. The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital; State Key Lab of Respiratory Disease; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. 4. State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Science, Beijing, China. 5. Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China. 6. Georgia Prevention Institute, Augusta University, Augusta, GA, USA. 7. Robert S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, USA. 8. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, USA. 9. Department of Anesthesiology and Perioperative Medicine, Augusta University, Augusta, GA, USA.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Daniel G Sedding; Monique Tröbs; Fabian Reich; Gerhard Walker; Ludger Fink; Werner Haberbosch; Wigbert Rau; Harald Tillmanns; Klaus T Preissner; Rainer M Bohle; Alexander C Langheinrich Journal: Circ Res Date: 2009-04-16 Impact factor: 17.367
Authors: Kalima B Timizheva; Abdulbary A M Ahmed; Amira Ait Aissa; Anna V Aghajanyan; Leyla V Tskhovrebova; Madina M Azova Journal: Life (Basel) Date: 2022-02-07