Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart

Abstract Background Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca 2 + /calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of...

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Published in:International journal of cardiology 2015-02, Vol.181, p.288-296
Main Authors: Bell, James R, Raaijmakers, Antonia J.A, Curl, Claire L, Reichelt, Melissa E, Harding, Tristan W, Bei, Aier, Ng, Dominic C.H, Erickson, Jeffrey R, Vila Petroff, Martin, Harrap, Stephen B, Delbridge, Lea M.D
Format: Article
Language:English
Subjects:
Animals
Arrhythmias, Cardiac - enzymology
Arrhythmias, Cardiac - genetics
Ca2 + regulation
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Cardiac myocytes
Cardiovascular
Female
Ischemia/reperfusion
Male
Myocardial Reperfusion Injury - enzymology
Myocardial Reperfusion Injury - genetics
Phosphorylation - physiology
Protein Isoforms - genetics
Protein Isoforms - metabolism
Rats
Rats, Sprague-Dawley
Sex Characteristics
Sex-specific
Signal Transduction - physiology
Ventricular arrhythmia
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Summary:Abstract Background Ischemia-related arrhythmic incidence is generally lower in females (vs males), though risk is selectively increased in women with underlying cardiopathology. Ca 2 + /calmodulin dependent kinase II (CaMKII) has been implicated in ischemia/reperfusion arrhythmias, yet the role of CaMKII in the ischemic female heart has not been determined. The aim of this study was to define the role and molecular mechanism of CaMKII activation in reperfusion arrhythmias in male/female hearts. Methods and results Male and female rat hearts and cardiomyocytes were subjected to multiple arrhythmogenic challenges. An increased capacity to upregulate autophosphorylated CaMKII (P-CaMKII) in Ca 2 + -challenged female hearts was associated with an enhanced ability to maintain diastolic function. In ischemia/reperfusion, female hearts (vs male) exhibited less arrhythmias (59 ± 18 vs 548 ± 9, s, p < 0.05), yet had augmented P-CaMKII (2.69 ± 0.30 vs 1.50 ± 0.14, rel. units, p < 0.05) and downstream phosphorylation of phospholamban (1.71 ± 0.42 vs 0.90 ± 0.10, p < 0.05). In contrast, hypertrophic female hearts had more reperfusion arrhythmias and lower phospholamban phosphorylation. Isolated myocyte experiments (fura-2) confirmed Ca 2 + -handling arrhythmogenic involvement. Molecular analysis showed target specificity of CaMKII was determined by post-translational modification, with CaMKIIδB and CaMKIIδC splice variants selectively co-localized with autophosphorylation and oxidative modifications of CaMKII respectively. Conclusions This study provides new mechanistic evidence that CaMKIIδ splice variants are selectively susceptible to autophosphorylation/oxidation, and that augmented generation of P-CaMKIIδB (Thr287) is associated with arrhythmia suppression in the female heart. Collectively these findings indicate that therapeutic approaches based on selective CaMKII splice form targeting may have potential benefit, and that sex-selective CaMKII intervention strategies may be valid.
ISSN:0167-5273
1874-1754
DOI:10.1016/j.ijcard.2014.11.159