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

Leandro Sommese, Carlos A. Valverde, Paula Blanco, María Cecilia Castro, Omar Velez Rueda, Marcia Kaetzel, John Dedman, Mark Anderson, Alicia Mattiazzi, Julieta Palomeque

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)394-406
Number of pages13
JournalInternational Journal of Cardiology
Volume202
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ryanodine Receptor Calcium Release Channel
Rodentia
Phosphorylation
Reactive Oxygen Species
Fructose
Diet
Prediabetic State
Glucose Intolerance
Heart Failure
Sarcoplasmic Reticulum
Protein Kinase Inhibitors
Cardiac Myocytes
Muscle Cells
Type 2 Diabetes Mellitus
Hypertrophy
Echocardiography
Cardiac Arrhythmias
Heart Diseases
Electrocardiography

Keywords

  • Arrhythmias
  • CaMKII
  • Impaired glucose tolerance
  • Prediabetes
  • Ryanodine receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2 + release events in a rodent model of early stage diabetes : The arrhythmogenic substrate. / Sommese, Leandro; Valverde, Carlos A.; Blanco, Paula; Castro, María Cecilia; Rueda, Omar Velez; Kaetzel, Marcia; Dedman, John; Anderson, Mark; Mattiazzi, Alicia; Palomeque, Julieta.

In: International Journal of Cardiology, Vol. 202, 01.01.2016, p. 394-406.

Research output: Contribution to journalArticle

Sommese, Leandro ; Valverde, Carlos A. ; Blanco, Paula ; Castro, María Cecilia ; Rueda, Omar Velez ; Kaetzel, Marcia ; Dedman, John ; Anderson, Mark ; Mattiazzi, Alicia ; Palomeque, Julieta. / Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2 + release events in a rodent model of early stage diabetes : The arrhythmogenic substrate. In: International Journal of Cardiology. 2016 ; Vol. 202. pp. 394-406.
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T1 - Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca2 + release events in a rodent model of early stage diabetes

T2 - The arrhythmogenic substrate

AU - Sommese, Leandro

AU - Valverde, Carlos A.

AU - Blanco, Paula

AU - Castro, María Cecilia

AU - Rueda, Omar Velez

AU - Kaetzel, Marcia

AU - Dedman, John

AU - Anderson, Mark

AU - Mattiazzi, Alicia

AU - Palomeque, Julieta

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N2 - 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.

AB - 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.

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