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Increased oxidative stress and Ca MKII activity contribute to electro‐mechanical defects in cardiomyocytes from a murine model of Huntington's disease

2018; Wiley; Volume: 286; Issue: 1 Linguagem: Inglês

10.1111/febs.14706

1742-4658

Julliane V. Joviano‐Santos, Artur Santos‐Miranda, Ana Flávia Machado Botelho, Itamar Couto Guedes de Jesus, Jéssica Neves Andrade, Tatiane de Oliveira Barreto, Matheus P.S. Magalhães-Gomes, Priscila Aparecida Costa Valadão, Jáder Santos Cruz, Marília Martins Melo, Sílvia Guatimosim, Cristina Guatimosim,

Neurological disorders and treatments

Huntington's disease (HD) is a neurodegenerative genetic disorder. Although described as a brain pathology, there is evidence suggesting that defects in other systems can contribute to disease progression. In line with this, cardiovascular defects are a major cause of death in HD. To date, relatively little is known about the peripheral abnormalities associated with the disease. Here, we applied a range of assays to evaluate cardiac electro-mechanical properties in vivo, using a previously characterized mouse model of HD (BACHD), and in vitro, using cardiomyocytes isolated from the same mice. We observed conduction disturbances including QT interval prolongation in BACHD mice, indicative of cardiac dysfunction. Cardiomyocytes from these mice demonstrated cellular electro-mechanical abnormalities, including a prolonged action potential, arrhythmic contractions, and relaxation disturbances. Cellular arrhythmia was accompanied by an increase in calcium waves and increased Ca2+ /calmodulin-dependent protein kinase II activity, suggesting that disruption of calcium homeostasis plays a key part. We also described structural abnormalities in the mitochondria of BACHD-derived cardiomyocytes, indicative of oxidative stress. Consistent with this, imbalances in superoxide dismutase and glutathione peroxidase activities were detected. Our data provide an in vivo demonstration of cardiac abnormalities in HD together with new insights into the cellular mechanistic basis, providing a possible explanation for the higher cardiovascular risk in HD.