Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2 + release events in a rodent model of early stage diabetes: The arrhythmogenic substrate

SOMMESE L; VALVERDE CA; BLANCO P; CASTRO MC; VÉLEZ RUEDA JO; KAETZEL MA; DEDMAN JR; ANDERSON ME; MATTIAZZI A; PALOMEQUE J

INTERNATIONAL JOURNAL OF CARDIOLOGY

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2016 vol. 202 p. 394 - 406

0167-5273

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 Ca(2+) 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.OBJECTIVES: To prove the hypothesis that increased ROS and CaMKII activity contribute to heart failure and arrhythmogenic mechanisms in early stage diabetes.METHODS-RESULTS: Echocardiography, electrocardiography, biochemical and intracellular Ca(2+) (Ca(2+)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 Ca(2+)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 Ca(2+) during the burst of spontaneous Ca(2+)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 Ca(2+)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.