Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca^{2 +} release events in a rodent model of early stage diabetes: The arrhythmogenic substrate

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• 作者：Leandro Sommese^a ; Carlos A. Valverde^a ; Paula Blanco^b ; Marí ; a Cecilia Castro^c ; Omar Velez Rueda^a ; Marcia Kaetzel^d ; John Dedman^d ; Mark E. Anderson^e ; Alicia Mattiazzi^a ; Julieta Palomeque^a ; ^{julip@med.unlp.edu.ar" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AF ; atrial fibrillation ; AV ; atrioventricular ; Ca2  ; +i ; intracellular calcium ; CaiT ; intracellular calcium transient ; CaMKII ; Ca2  ; + calmodulin dependent protein kinase ; CaSp ; calcium sparks ; CaW ; calcium waves ; DAD ; delay afterdepolarizations ; EAD ; early afterdepolarizations ; ECG ; electrocardiogram ; LV ; left ventricle ; RyR2 ; ryanodine receptor 2 ; PLN ; phospholamban ; NCX ; sodium&ndash ; Ca2  ; + exchanger ; ROS ; reactive oxygen species ; SR ; sarcoplasmic reticulum ; T2DM ; type 2 diabetes me
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：202
• 期：Complete
• 页码：394-406
• 全文大小：1973 K

文摘

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.