2019
DOI: 10.1016/j.yjmcc.2018.11.019
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Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Abstract: Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection. While normal at 2 and 6 weeks, ejection fraction was significantly reduced at 15 weeks. In order to evaluate the underlying mechanisms, we… Show more

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Cited by 38 publications
(33 citation statements)
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“…Furthermore, experimental examinations of the calcium/calmodulin-dependent protein kinase revealed its role in disturbing calcium balance through promoting SR calcium leakage (Little et al, 2009;Sag et al, 2011). In mice chronically treated with DOX, heart dysfunction occurred at 15 weeks, which may be due to a depressed [Ca 21 ] i transient (Llach et al, 2019). In another study, mechanical unloading helped increase functional sarcoplasmic reticulum Ca 21 ATPase and improved [Ca 21 ] i handling and contractility in rats with DOX-induced cardiomyopathy (Takaseya et al, 2004).…”
Section: Molecular Mechanisms Of Dicmentioning
confidence: 99%
“…Furthermore, experimental examinations of the calcium/calmodulin-dependent protein kinase revealed its role in disturbing calcium balance through promoting SR calcium leakage (Little et al, 2009;Sag et al, 2011). In mice chronically treated with DOX, heart dysfunction occurred at 15 weeks, which may be due to a depressed [Ca 21 ] i transient (Llach et al, 2019). In another study, mechanical unloading helped increase functional sarcoplasmic reticulum Ca 21 ATPase and improved [Ca 21 ] i handling and contractility in rats with DOX-induced cardiomyopathy (Takaseya et al, 2004).…”
Section: Molecular Mechanisms Of Dicmentioning
confidence: 99%
“…It also suggested that DOX affect the transcription of various genes encoding Ca 2+ regulating proteins, SERCA2 and RYR2 (cardiac SR Ca 2+ pump), phospholamban, calsequestrin, and Bmax of RYR2. [89][90][91][92] However, some researchers have reported the downregulated expression of Ca 2+ transporter genes in SR, which is responsible for impaired Ca 2+ homeostasis and hence can lead to deformities in EC machinery. 93,94 Recent studies have demonstrated that a direct activation of PPAR by GW0742 ends in a higher phosphorylation of TnI and improves cardiac performance as well.…”
Section: Dox and Calcium Regulationmentioning
confidence: 99%
“…Studies on the extended exposures to drug‐influencing left ventricular fractional shortening, reduction of ejection fraction, and dilation have elucidated a straightforward depression in the [Ca 2+ ] transients. It also suggested that DOX affect the transcription of various genes encoding Ca 2+ regulating proteins, SERCA2 and RYR2 (cardiac SR Ca 2+ pump), phospholamban, calsequestrin, and Bmax of RYR2 89‐92 93,94 .…”
Section: Dox and Calcium Regulationmentioning
confidence: 99%
“…En nuestro estudio las VE-MSC se administraron junto con el fármaco con el objetivo de evaluar la potencial capacidad de prevención de la cardiotoxicidad, a diferencia de los estudios que evalúan el efecto terapéutico de éstas para revertir el daño causado por doxorubicina una vez ha sido inducido (171), pues son muchos los estudios que evalúan el efecto dañino de la administración del fármaco días o incluso semanas después (175,186,215). Yang et al evaluaron también el efecto protector de los exosomas procedentes de BM-MSC pre-tratando las células madre cardíacas durante 24 horas antes de inducir estrés oxidativo por H2O2 (213).…”
Section: Discussionunclassified
“…De acuerdo con un estudio reciente en el que evalúan la actividad pulsátil in vitro en cardiomiocitos murinos adultos (183) e in vivo en ratones (183,186), mostramos que la exposición aguda a la doxorubicina altera la contractilidad de los cardiomiocitos reduciendo el número de pulsaciones. Alteraciones similares en la función contráctil de los cardiomiocitos, debidas a variaciones en los niveles intracelulares de calcio, se detectaron también tras dosis acumulativas de doxorubicina en un modelo murino (186). La función contráctil es un mecanismo dependiente de ATP y Ca 2+ .…”
Section: Discussionunclassified