Doxorubicin Cardiac Dysfunction: Effects on Calcium Regulatory Proteins, Sarcoplasmic Reticulum, and Triiodothyronine

Olson, Richard D.; Gambliel, Hervé A.; Vestal, Robert E.; Shadle, Susan E.; Charlier, Henry A.; Cusack, Barry J.

doi:10.1385/ct:5:3:269

Cited by 55 publications

(49 citation statements)

References 40 publications

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“…Furthermore, doxorubicin reduced NCX1 expression (Fig. 4D), in agreement with previous findings showing similar effects in atrial and ventricular preparations isolated from doxorubicin-treated rabbits (Olson et al, 2005) and in dog heart sarcolemmal vesicles (Caroni et al, 1981). Collectively, the reduction in SERCA2 and NCX1 expression can explain the elevated diastolic [Ca 2ϩ ] i and the slowing of [Ca 2ϩ ] i relaxation kinetics, as well as reduced rate of myocyte relaxation caused by doxorubicin.…”

Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onsupporting

confidence: 91%

“…Doxorubicin decreased the expression of SERCA2 and NCX1, but did not affect the expression of RyR, calsequestrin, or phospholamban. Accordingly, previous studies showed that doxorubicin decreased SERCA2 mRNA and protein expression in cultured NRVM (Arai et al, 2000), adult rat ventricular cardiomyocytes (Timolati et al, 2006), and rabbit in vivo model of doxorubicin cardiotoxicity (Arai et al, 1998;Olson et al, 2005). Furthermore, doxorubicin reduced NCX1 expression (Fig.…”

Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onmentioning

confidence: 77%

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TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administrationapproved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptoticinducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicininduced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 M, 24 h) prevented doxorubicin (0.5 M, 24 h)-induced elevation of diastolic [Ca 2ϩ ] i , the slowing of [Ca 2ϩ ] i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca 2ϩ ) ATPase, Na ϩ /Ca 2ϩ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/ dt max ) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with doxorubicin in the treatment of malignancies in humans.

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Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onsupporting

confidence: 91%

Section: Tvp1022 Attenuated the Deleterious Effects Of Doxorubicin Onmentioning

confidence: 77%

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Berdichevski

Meiry²,

Milman³

et al. 2009

J Pharmacol Exp Ther

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“…DOX has been consistently found to decrease SERCA2a mRNA and protein levels (Arai et al, 1998;Olson et al, 2005;Richard et al, 2011), and SERCA2a impairment is closely associated with decreased heart contractility in DOX cardiotoxicity (Frank et al, 2003;Periasamy & Huke, 2001). In this study, DOX treatment caused significant decrease (p50.05) of SERCA2a mRNA expression level in the DOX only-treated group which can partially explain the rise of cytosolic and mitochondrial calcium levels.…”

Section: Discussionsupporting

confidence: 52%

“…Several studies have proved that reactive oxygen species resulted from DOX treatment has either direct or indirect effect to calcium regulatory proteins (Arai et al, 1998;Olson et al, 2005;Richard et al, 2011). Arai et al (2000) demonstrated the effect of DOX to the expression and activity of SERCA2a, a calcium pump responsible for calcium influx from cytosol to sarcoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

Agustini¹,

Arozal

Louisa

et al. 2015

Pharmaceutical Biology

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Context: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. Objective: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. Materials and methods: Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-a), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. Results: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-a by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p50.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p40.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. Discussion and conclusion: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis. ARTICLE HISTORY

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“…3f,g). SERCA-2a is a molecular target in DOX toxicity 45 . DOX (1 mM) caused an increase in t (that is, slower Ca 2 þ reuptake), which was reversed by adenoviral transduction of ILK WT (Fig.…”

Section: Resultsmentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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Doxorubicin Cardiac Dysfunction: Effects on Calcium Regulatory Proteins, Sarcoplasmic Reticulum, and Triiodothyronine

Cited by 55 publications

References 40 publications

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

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