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

SOMESSE, L; VALVERDE, CA; BLANCO, P; CASTRO, C; VELEZ RUEDA, O; KAETZEL, M; DEDMAN, J; ANDERSON, ME; MATTIAZZI , A; PALOMEQUE, J

INTERNATIONAL JOURNAL OF CARDIOLOGY

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2015 vol. 202 p. 394 - 406

0167-5273

Background: Heart failure and arrhythmias occur more frequently in patients with type 2 diabetes (T2DM) thanin the general population. T2DMis preceded by a prediabetic condition marked by elevated reactive oxygen species(ROS) and subclinical cardiovascular defects. Although multifunctional Ca2+ calmodulin-dependent proteinkinase II (CaMKII) is ROS-activated and CaMKII hyperactivity promotes cardiac diseases, a link between prediabetesand CaMKII in the heart is unprecedented.Objectives: To prove the hypothesis that increased ROS and CaMKII activity contribute to heart failure and arrhythmogenicmechanisms in early stage diabetes.Methods?Results: Echocardiography, electrocardiography, biochemical and intracellular Ca2+ (Ca2+i) determinationswere 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) phosphorylationcompared to rats fed with control diet. Isolated cardiomyocytes from fructose-rich diet showed increasedspontaneous 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 myocytesshowed increased diastolic Ca2+ during the burst of spontaneous Ca2+i release events.Mice treatedwith Tempolor with sarcoplasmic reticulum-targeted CaMKII-inhibition by transgenic expression of the CaMKII inhibitorypeptide AIP, were protected fromfructose-rich diet-induced spontaneous Ca2+i release events, spontaneous contractionsand arrhythmogenesis in vivo, despite ROS increases.Conclusions: RyR2 phosphorylation by ROS-activated CaMKII, contributes to impaired glucose tolerance-inducedarrhythmogenic mechanisms, suggesting that CaMKII inhibition could prevent prediabetic cardiovascular complicationsand/or evolution.