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.

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 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: Leandro Sommese, Carlos A Valverde, Paula Blanco, María Cecilia Castro, Omar Velez Rueda, Marcia Kaetzel, John Dedman, Mark E Anderson, Alicia Mattiazzi, Julieta Palomeque
• Journal: International journal of cardiology (Int J Cardiol) Vol. 202 Pg. 394-406 (Jan 01 2016) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 26432489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Ireland Ltd.

Chemical References

• Amino Acids
• Benzylamines
• Nicotinic Acids
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Ryanodine Receptor Calcium Release Channel
• Sulfonamides
• glucose tolerance factor
• Chromium
• KN 93
• Fructose
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium

Topics

• Amino Acids (metabolism)
• Animals
• Arrhythmias, Cardiac (metabolism, pathology, prevention & control)
• Benzylamines (pharmacology)
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (chemistry, metabolism)
• Chromium (metabolism)
• Diabetes Mellitus, Type 2 (metabolism, pathology)
• Disease Models, Animal
• Fructose (administration & dosage)
• Heart Failure (metabolism, pathology, prevention & control)
• Male
• Mice
• Myocytes, Cardiac (metabolism)
• Nicotinic Acids (metabolism)
• Phosphorylation
• Prediabetic State (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Sulfonamides (pharmacology)