title: Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca(2+) release events in a rodent model of early stage diabetes: The arrhythmogenic substrate.
abstract: BACKGROUND
  Heart failure and arrhythmias occur more frequently in patients with type 2 diabetes (T2DM) than in the general population. T2DM is preceded by a prediabetic condition marked by elevated reactive oxygen species (ROS) and subclinical cardiovascular defects. Although multifunctional Ca2+ calmodulin-dependent protein kinase II (CaMKII) is ROS-activated and CaMKII hyperactivity promotes cardiac diseases, a link between prediabetes and CaMKII in the heart is unprecedented.
  
  
  OBJECTIVE
  To prove the hypothesis that increased ROS and CaMKII activity contribute to heart failure and arrhythmogenic mechanisms in early stage diabetes.
  
  
  RESULTS
  Echocardiography, electrocardiography, biochemical and intracellular Ca2+ (Ca2+i) determinations were performed in fructose-rich diet-induced impaired glucose tolerance, a prediabetes model, in rodents. Fructose-rich diet rats showed decreased contractility and hypertrophy associated with increased CaMKII activity, ROS production, oxidized CaMKII and enhanced CaMKII-dependent ryanodine receptor (RyR2) phosphorylation compared to rats fed with control diet. Isolated cardiomyocytes from fructose-rich diet showed increased spontaneous Ca2+i release events associated with spontaneous contractions, which were prevented by KN-93, a CaMKII inhibitor, or addition of Tempol, a ROS scavenger, to the diet. Moreover, fructose-rich diet myocytes showed increased diastolic Ca2+ during the burst of spontaneous Ca2+i release events. Mice treated with Tempol or with sarcoplasmic reticulum-targeted CaMKII-inhibition by transgenic expression of the CaMKII inhibitory peptide AIP, were protected from fructose-rich diet-induced spontaneous Ca2+i release events, spontaneous contractions and arrhythmogenesis in vivo, despite ROS increases.
  
  
  CONCLUSIONS
  RyR2 phosphorylation by ROS-activated CaMKII, contributes to impaired glucose tolerance-induced arrhythmogenic mechanisms, suggesting that CaMKII inhibition could prevent prediabetic cardiovascular complications and/or evolution.
authors.affiliation: Centro de Investigaciones Cardiovasculares, CONICET-La Plata 1900, Facultad de Medicina, UNLP, Argentina.
authors.forename: Leandro
authors.initials: L
authors.lastname: Sommese
authors.affiliation: Centro de Investigaciones Cardiovasculares, CONICET-La Plata 1900, Facultad de Medicina, UNLP, Argentina.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Valverde
authors.affiliation: Servicio de Ecocardiografía, Facultad de Veterinaria, UNLP, La Plata 1900, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Blanco
authors.affiliation: CENEXA, Centro Experimental de Endocrinología y Aplicada (UNLP-CONICET La Plata), Facultad de Ciencias Médicas, UNLP, La Plata 1900, Argentina.
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Castro
authors.affiliation: Centro de Investigaciones Cardiovasculares, CONICET-La Plata 1900, Facultad de Medicina, UNLP, Argentina.
authors.forename: Omar Velez
authors.initials: OV
authors.lastname: Rueda
authors.affiliation: Department of Genome Science, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Kaetzel
authors.affiliation: Department of Genome Science, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
authors.forename: John
authors.initials: J
authors.lastname: Dedman
authors.affiliation: University of Iowa, 285 Newton Rd, CBRB 2256, Iowa City, IA 52242, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Centro de Investigaciones Cardiovasculares, CONICET-La Plata 1900, Facultad de Medicina, UNLP, Argentina.
authors.forename: Alicia
authors.initials: A
authors.lastname: Mattiazzi
authors.affiliation: Centro de Investigaciones Cardiovasculares, CONICET-La Plata 1900, Facultad de Medicina, UNLP, Argentina. Electronic address: julip@med.unlp.edu.ar.
authors.forename: Julieta
authors.initials: J
authors.lastname: Palomeque
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry / Q000378:metabolism*; D002857:Chromium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005632:Fructose / Q000008:administration & dosage; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D009539:Nicotinic Acids / Q000378:metabolism; D010766:Phosphorylation; D011236:Prediabetic State / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000596:Amino Acids; D001596:Benzylamines; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002857:Chromium; D005632:Fructose; D009539:Nicotinic Acids; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; C015240:glucose tolerance factor; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: Arrhythmias; CaMKII; Impaired glucose tolerance; Prediabetes; Ryanodine receptor