The role of CaMKII in diabetic heart dysfunction

Daniels, Lorna J.; Bell, James; Delbridge, L.; McDonald, Fiona J.; Lamberts, Regis R.; Erickson, Jeffrey R.

doi:10.1007/s10741-015-9498-3

Cited by 30 publications

(28 citation statements)

References 158 publications

(146 reference statements)

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“…It is well known that the cardiac excitation-contraction coupling is highly dependent on Ca 2+ transient, that is handled through an array of ion channels, antiporters and pumps that are finally regulated, at post-translational level, by phosphorylation. Many kinases have been implicated in the regulation of Ca 2+ transient, such as PKA, CamKII and PKC [47][48][49]. New findings highlight the role, overlooked for many years, of phosphatases in the fine tuning of the phosphorylation balance of physiologically relevant targets [45,50,51].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

Bocchi

Savi

Naponelli

et al. 2018

Cell Physiol Biochem

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Background/Aims: Dietary polyphenols from green tea have been shown to possess cardio-protective activities in different experimental models of heart diseases and age-related ventricular dysfunction. The present study was aimed at evaluating whether long term in vivo administration of green tea extracts (GTE), can exert positive effects on the normal heart, with focus on the underlying mechanisms. Methods: The study population consisted of 20 male adult Wistar rats. Ten animals were given 40 mL/day tap water solution of GTE (concentration 0.3%) for 4 weeks (GTE group). The same volume of water was administered to the 10 remaining control rats (CTRL). Then, in vivo and ex vivo measurements of cardiac function were performed in the same animal, at the organ (hemodynamics) and cellular (cardiomyocyte mechanical properties and intracellular calcium dynamics) levels. On cardiomyocytes and myocardial tissue samples collected from the same in vivo studied animals, we evaluated: (1) the intracellular content of ATP, (2) the endogenous mitochondrial respiration, (3) the expression levels of the Sarcoplasmic Reticulum Ca²⁺-dependent ATPase 2a (SERCA2), the Phospholamban (PLB) and the phosphorylated form of PLB, the L-type Ca²⁺ channel, the Na⁺-Ca²⁺ exchanger, and the ryanodine receptor 2. Results: GTE cardiomyocytes exhibited a hyperdynamic contractility compared with CTRL (the rate of shortening and re-lengthening, the fraction of shortening, the amplitude of calcium transient, and the rate of cytosolic calcium removal were significantly increased). A faster isovolumic relaxation was also observed at the organ level. Consistent with functional data, we measured a significant increase in the intracellular ATP content supported by enhanced endogenous mitochondrial respiration in GTE cardiomyocytes, as well as higher values of the ratios phosphorylated-PLB/PLB and SERCA2/PLB. Conclusions: Long-term in vivo administration of GTE improves cell mechanical properties and intracellular calcium dynamics in normal cardiomyocytes, by increasing energy availability and removing the inhibitory effect of PLB on SERCA2.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

Bocchi

Savi

Naponelli

et al. 2018

Cell Physiol Biochem

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“…Overexpression of GlcNAcase or inhibition of GlcNAc modification increased expression of SERCA2a, ablated sarcoplasmic reticulum Ca ++ leak, improved cardiac contractility, and reduced arrhythmic events. Increased levels of ROS also cause autonomous activation of CaMKII by oxidation of adjacent methionine residues in its regulatory domain 50 . Activation of this mitochondrial ROS-oxidized CaMKII pathway increased mortality after myocardial infarction in diabetic mouse models 8 .…”

Section: Biochemical Molecular and Cellular Mechanismsmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Shah

Brownlee

2016

Circulation Research

480

343

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The clinical correlations linking diabetes with accelerated atherosclerosis, cardiomyopathy, and increased post-MI fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in ROS production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP ribose) polymerase (PARP), which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and PARP also reduce sirtuin, PGC1α, and AMPK activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of pro-atherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, PAD4, and activates the NRLP3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of FOXO1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after MI by increasing post-translational protein modifications which cause increased ryanodine receptor phosphorylation and downregulation of SERCA2a transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

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“…The combined effects enhance NCX activity in the reverse mode and lead to Ca i overload. The interactions are implicated in the initiation of early and delayed afterdepolarizations . The effects of CaMKII prolong APD and Ca 2+ transient duration through slow inactivation of I Na , increase amplitude and slow inactivation of L‐type Ca 2+ currents, and further enhanced arrhythmogenic afterdepolarization.…”

Section: Discussionmentioning

confidence: 99%