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These increases were prevented by CaMKII inhibition.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>FRD significantly augmented cardiac apoptosis in WT <jats:italic>vs<\/jats:italic>. CD\u2010WT mice, which was prevented by co\u2010treatment with the reactive oxygen species scavenger Tempol. Oxidative stress was also increased in FRD\u2010SR\u2010autocamide inhibitory peptide (AIP) mice, expressing the SR\u2010targeted CaMKII inhibitor AIP, without any significant enhancement of apoptosis <jats:italic>vs<\/jats:italic>. CD\u2010SR\u2010AIP mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>FRD produced mitochondrial swelling and membrane depolarization in FRD\u2010WT mice but not in FRD\u2010S2814A mice, in which the CaMKII site on ryanodine receptor 2 was ablated.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>FRD decreased mitochondrial area, mean Feret diameter and the mean distance between SR and the outer mitochondrial membrane <jats:italic>vs<\/jats:italic>. CD hearts. This remodelling was prevented in AC3I mice, with cardiac\u2010targeted CaMKII inhibition.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The impact of cardiac apoptosis in pre\u2010diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose\u2010rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca<jats:sup>2+<\/jats:sup> leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre\u2010diabetes. We generated a pre\u2010diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca<jats:sup>2+<\/jats:sup> spontaneous events in the absence of SR Ca<jats:sup>2+<\/jats:sup> load alterations <jats:italic>vs<\/jats:italic>. control\u2010diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [<jats:sup>3<\/jats:sup>H]ryanodine binding and CaMKII phosphorylation of RyR2\u2010S2814 residue <jats:italic>vs<\/jats:italic>. normoglycaemia. CaMKII inhibition prevented hyperglycaemia\u2010induced alterations. FRD also evoked cardiac apoptosis in WT mice <jats:italic>vs<\/jats:italic>. CD\u2010WT mice. Co\u2010treatment with the reactive oxygen species scavenger Tempol prevented FRD\u2010induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD\u2010SR\u2010AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR\u2013mitochondrial distance <jats:italic>vs<\/jats:italic>. CD\u2010WT hearts. This remodelling was prevented in AC3I mice, with cardiac\u2010targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca<jats:sup>2+<\/jats:sup> leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre\u2010diabetic heart. The FRD\u2010induced decrease in SR\u2013mitochondrial distance is likely to additionally favour Ca<jats:sup>2+<\/jats:sup> transit between the two organelles.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp273714","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T09:49:49Z","timestamp":1484905789000},"page":"4089-4108","source":"Crossref","is-referenced-by-count":69,"title":["Calcium\u2010calmodulin\u2010dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance"],"prefix":"10.1113","volume":"595","author":[{"given":"Marilen","family":"Federico","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares, CCT\u2010La Plata\u2010CONICET Facultad de Cs. 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