Increased oxidative stress and CaMKII activity contributeto electro-mechanical defects in cardiomyocytes from amurine model of Huntington’s disease
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2019
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Huntington’s disease (HD) is a neurodegenerative genetic disorder.Although described as a brain pathology, there is evidence suggesting thatdefects in other systems can contribute to disease progression. In line withthis, cardiovascular defects are a major cause of death in HD. To date, rel-atively little is known about the peripheral abnormalities associated withthe disease. Here, we applied a range of assays to evaluate cardiac electro-mechanical properties in vivo, using a previously characterized mousemodel of HD (BACHD), and in vitro, using cardiomyocytes isolated fromthe same mice. We observed conduction disturbances including QT intervalprolongation in BACHD mice, indicative of cardiac dysfunction. Car-diomyocytes from these mice demonstrated cellular electro-mechanicalabnormalities, including a prolonged action potential, arrhythmic contrac-tions, and relaxation disturbances. Cellular arrhythmia was accompaniedby an increase in calcium waves and increased Ca 2+ /calmodulin-dependentprotein kinase II activity, suggesting that disruption of calcium homeostasisplays a key part. We also described structural abnormalities in the mito-chondria of BACHD-derived cardiomyocytes, indicative of oxidative stress.Consistent with this, imbalances in superoxide dismutase and glutathioneperoxidase activities were detected. Our data provide an in vivo demonstra-tion of cardiac abnormalities in HD together with new insights into the cel-lular mechanistic basis, providing a possible explanation for the highercardiovascular risk in HD.AbbreviationsAP, action potential; APR 90% , 90% AP repolarization; CaMKII, Ca 2+/calmodulin-dependent protein kinase II; CAT, catalase; DCF,dichlorodihydrofluorescein diacetate; ECG, electrocardiography; F0, baseline fluorescence; F, fluorescence; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GPx, glutathione peroxidase; HD, Huntington’s disease; Htt, huntingtin gene; HTT, huntingtin; mHTT, mutantHuntingtin; PB, sodium phosphate buffer; PLN, phospholamban; polyQ, polyglutamine; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca 2+-ATPase; SOD, superoxide dismutase; SR, sarcoplasmic reticulum.110 The FEBS Journal 286 (2019) 110–123 ª 2018 Federation of European Biochemical Societies
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Action potential, Arrhythmia, CaMKII, Huntington’s disease, Oxidative damage
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JOVIANO-SANTOS, Julliane Vasconcelos et al. Increased oxidative stress and CaMKII activity contributeto electro-mechanical defects in cardiomyocytes from amurine model of Huntington’s disease. The FEBS Journal, Cambridge, v. 286, n. 1, p. 110–123, 2019. DOI: 10.1111/febs.14706. Disponível em: https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.14706. Acesso em: 16 maio 2025.