Accumulation of endogenous adenosine improves cardiomyocyte metabolism via epigenetic reprogramming in an ischemia-reperfusion model

Redox Biol. 2023 Nov:67:102884. doi: 10.1016/j.redox.2023.102884. Epub 2023 Sep 13.

Abstract

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.

Keywords: ADK; Adenosine; Epigenetics; IGF-1; Ischemia-reperfusion; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism
  • Animals
  • Apoptosis
  • DNA / metabolism
  • Epigenesis, Genetic
  • Glucose / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Ischemia / metabolism
  • Mice
  • Mice, Knockout
  • Myocardial Reperfusion Injury* / drug therapy
  • Myocardial Reperfusion Injury* / genetics
  • Myocardial Reperfusion Injury* / metabolism
  • Myocytes, Cardiac* / metabolism
  • Positron Emission Tomography Computed Tomography
  • Reperfusion

Substances

  • Adenosine
  • Insulin-Like Growth Factor I
  • DNA
  • Glucose