title: Epac2-Rap1 Signaling Regulates Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias.
abstract: OBJECTIVE
  In the heart, β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function. The aim of the present study was to investigate the influence of Epac2-Rap1 signaling on the heart using both in vivo and in vitro approaches.
  
  
  RESULTS
  Inhibition of Epac2 signaling induced early afterdepolarization arrhythmias in ventricular myocytes. The underlying mechanism involved an increase in mitochondrial reactive oxygen species (ROS) and activation of the late sodium current (INalate). Arrhythmias were blocked by inhibition of INalateor the mitochondria-targeted antioxidant, mitoTEMPO. In vivo, inhibition of Epac2 caused ventricular tachycardia, torsades de pointes, and sudden death. The in vitro and in vivo effects of Epac2 inhibition were mimicked by inhibition of geranylgeranyltransferase-1, which blocks interaction of Rap1 with downstream targets.
  
  
  METHODS
  Our findings show for the first time that Rap1 acts as a negative regulator of mitochondrial ROS production in the heart and that impaired Epac2-Rap1 signaling causes arrhythmias due to ROS-dependent activation of INalate. This has implications for the use of chemotherapeutics that target Epac2-Rap1 signaling. However, selective inhibition of INalateprovides a promising strategy to prevent arrhythmias caused by impaired Epac2-Rap1 signaling.
  
  
  CONCLUSIONS
  Epac2-Rap1 signaling attenuates mitochondrial ROS production and reduces myocardial arrhythmia susceptibility. Antioxid. Redox Signal. 27, 117-132.
authors.affiliation: 1 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: 1 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Kirton
authors.affiliation: 2 Division of Cardiovascular Medicine, Faculty of Medicine and Health, University of Leeds , Leeds, United Kingdom .
authors.forename: Moza
authors.initials: M
authors.lastname: Al-Owais
authors.affiliation: 3 PHYMEDEXP, Physiologie et Médecine Expérimentale, Cœur et Muscles, INSERM U1046, CNRS UMR 9214, Université de Montpellier , Montpellier, France .
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.affiliation: 3 PHYMEDEXP, Physiologie et Médecine Expérimentale, Cœur et Muscles, INSERM U1046, CNRS UMR 9214, Université de Montpellier , Montpellier, France .
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.affiliation: 2 Division of Cardiovascular Medicine, Faculty of Medicine and Health, University of Leeds , Leeds, United Kingdom .
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.affiliation: 1 Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds , Leeds, United Kingdom .
authors.forename: Derek S
authors.initials: DS
authors.lastname: Steele
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D020662:Guanine Nucleotide Exchange Factors; C430803:RAP1A protein, human; C442864:RAPGEF4 protein, human; D017382:Reactive Oxygen Species; D020827:rap1 GTP-Binding Proteins
keywords: Ca2+; Epac; ROS; Rap1; arrhythmias; cardiac