Role of NOX2 in mediating doxorubicin-induced senescence in human endothelial progenitor cells

Falco, Elena De; Carnevale, Roberto; Pagano, Francesca; Chimenti, Isotta; Fianchini, Luca; Bordin, Antonella; Siciliano, Camilla; Monticolo, Roberto; Equitani, Francesco; Carrizzo, Albino; Peruzzi, Mariangela; Vecchione, Carmine; Rubattu, Speranza; Sciarretta, Sebastiano; Frati, Giacomo

doi:10.1016/j.mad.2016.05.004

Cited by 33 publications

(31 citation statements)

References 48 publications

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“…This information adds to the knowledge about the effects of 5FU on the cardiovascular system. More generally, it highlights that anticancer treatment-induced senescence of endothelial cells, which so far has mainly been described and discussed for doxorubicin (Spallarossa et al, 2010;Hodjat et al, 2013;De Falco et al, 2016) and ionizing radiation (Azimzadeh et al, 2015;Park et al, 2016), may also be relevant for other oncological therapies. In the heart, 5FU-initiated senescence might at least in part contribute to coronary spasm and/or microvascular disease and might promote the formation and progression of coronary atherosclerotic lesions, as endothelial senescence has been implicated in atherogenesis (Yin and Pickering, 2016).…”

Section: Discussionmentioning

confidence: 99%

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Altieri

Murialdo

Barisione

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSE5-fluorouracil (5FU) and its prodrug, capecitabine, can damage endothelial cells, whilst endothelial integrity is preserved by glucagon-like peptide 1 (GLP-1). Here, we studied the effect of 5FU on endothelial senescence and whether GLP-1 antagonizes it. EXPERIMENTAL APPROACHEA.hy926 cells were exposed to 5FU or sera from patients taking capecitabine, with or without pre-incubation with GLP-1. Senescence was identified by expression of senescence-associated β-galactosidase and p16INK4a and reduced cell proliferation. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and CD146 (marker of endothelial injury) were measured by ELISA before and at completion of capecitabine chemotherapy. RT-PCR, western blotting, functional experiments with signalling inhibitors and ERK1/2 silencing were performed to characterize 5FU-induced phenotype and elucidate the pathways underlying 5FU and GLP-1 activity. KEY RESULTSBoth 5FU and sera from capecitabine-treated patients stimulated endothelial cell senescence. 5FU-elicited senescence occurred via activation of p38 and JNK, and was associated with decreased eNOS and SIRT-1 levels. Furthermore, 5FU up-regulated VCAM1 and TYMP (encodes enzyme activating capecitabine and 5FU), and sVCAM-1 and CD146 concentrations were higher after than before capecitabine chemotherapy. A non-significant trend for higher ICAM1 levels was also observed. GLP-1 counteracted 5FU-initiated senescence and reduced eNOS and SIRT-1 expression, this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K. CONCLUSIONS AND IMPLICATIONS5FU causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects. 5FU-triggered senescence was prevented by GLP-1, raising the possibility of using GLP-1 analogues and degradation inhibitors to treat 5FU and capecitabine vascular toxicity.

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Section: Discussionmentioning

confidence: 99%

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Altieri

Murialdo

Barisione

et al. 2017

British J Pharmacology

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“…D Cappetta et al Falco et al, 2016). Genetic disruption of NOX2 is known to protect against doxorubicin cardiotoxicity, while doxorubicin-treated wild-type mice display NOX2 and NOX4 up-regulation and increased oxidase activity (Deng et al, 2007;Zhao et al, 2010).…”

Section: Bjpmentioning

confidence: 99%

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Cappetta

Esposito

Coppini

et al. 2017

British J Pharmacology

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Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. EXPERIMENTAL APPROACHFischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg À1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg À1 , daily) for the following 4 weeks. KEY RESULTSWhile diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. CONCLUSIONS AND IMPLICATIONSRanolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. LINKED ARTICLES

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“…Endogenous NO biosynthesis has a significant effect on the biological function of EPCs (36). The modulation of NADPH oxidase 2 in human EPCs can restore its physiological function and properties (37). During prehypertension, NO production by early EPCs, which is associated with EPC-mediated endothelial repair capacity (38,39), is markedly decreased (11).…”

Section: Discussionmentioning

confidence: 99%

Endothelial progenitor cell impairment mediated vasodilation dysfunction via diminishing nitric oxide production in postmenopausal females

Wang

et al. 2019

Mol Med Report

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Role of NOX2 in mediating doxorubicin-induced senescence in human endothelial progenitor cells

Cited by 33 publications

References 48 publications

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Endothelial progenitor cell impairment mediated vasodilation dysfunction via diminishing nitric oxide production in postmenopausal females

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