Accumulation of endogenous adenosine improves cardiomyocyte metabolism via epigenetic reprogramming in an ischemia-reperfusion model
Peng Wang,
Rifeng Gao,
Tingting Wu,
Jinyan Zhang,
Xiaolei Sun,
Fan Fan,
Cong Wang,
Sanli Qian,
Bingyu Li,
Yunzeng Zou,
Yuqing Huo,
John Fassett,
Yingjie Chen,
Junbo Ge,
Aijun Sun
Affiliations
Peng Wang
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Rifeng Gao
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Cardiac Surgery Department, The Second Affiliated Hospital Zhejiang University School of Medicine, China
Tingting Wu
Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
Jinyan Zhang
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Xiaolei Sun
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Fan Fan
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Cong Wang
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Sanli Qian
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Bingyu Li
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Yunzeng Zou
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Yuqing Huo
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
John Fassett
Department of Pharmacology and Toxicology, University of Graz, 8010, Graz, Austria
Yingjie Chen
Department of Physiology & Biophysics, University Mississippi Medical Center, MS, 39216, USA
Junbo Ge
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
Aijun Sun
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Corresponding author. Room 205, Building No.19, No. 18 of Road Fenglin, District Xuhui, Shanghai, USA.
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
