SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells

Angelis, Antonella De; Piegari, Elena; Cappetta, Donato; Russo, Rosa; Esposito, Grazia; Ciuffreda, Loreta Pia; Ferraiolo, Fiorella Angelica Valeria; Frati, Caterina; Fagnoni, Francesco; Berrino, Liberato; Quaini, Federico; Rossi, Francesco; Urbanek, Konrad

doi:10.1016/j.ijcard.2015.03.438

Cited by 68 publications

(81 citation statements)

References 77 publications

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“…By immunofluorescence, injected cells were detected by GFP antibody (Abcam, Cambridge, UK) [32]. Cycling epithelial and smooth muscle cells (SMCs) were identified by Ki67 labeling (Vector Laboratories, Burlingame, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

Spaziano

Cappetta

Urbanek

et al. 2016

Mediators of Inflammation

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Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGFβ were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness.

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Section: Methodsmentioning

confidence: 99%

New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

Spaziano

Cappetta

Urbanek

et al. 2016

Mediators of Inflammation

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“…Rats (n = 45) received six i.p. injections of 2.5 mg·kg À1 of doxorubicin, every other day, over a period of 2 weeks to reach a cumulative dose of 15 mg·kg À1 (De Angelis et al, 2015).…”

Section: Animal Protocolsmentioning

confidence: 99%

“…Extracellular matrix remodelling and interstitial fibrosis are constantly present in the development and progression of doxorubicin cardiotoxicity (De Angelis et al, 2015;Cappetta et al, 2016). Therefore, the effects of ranolazine on doxorubicin-induced extracellular matrix remodelling and fibrosis was evaluated.…”

Section: Effects Of Ranolazine On Myocardial Remodellingmentioning

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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“…The functional inferiority of hCPCs exposed to DOX was confirmed in vivo in an animal model of anthracycline cardiomyopathy. In contrast to experimental therapy with healthy cells, the use of DOX-treated hCPCs did not lead to structural and functional recovery and the survival benefits were not observed [58].…”

Section: Dox and Functional Properties Of Cpcsmentioning

confidence: 78%

“…Furthermore, senescence of stem cell population contributes to the onset and progression of heart failure [47][48][49][51][52][53][54]. In this view, relatively recent studies have shown that cardiotoxicity of the anthracycline is not restricted to cardiomyocytes but affects also resident CPCs, proposing an additional mechanism underlining the pathophysiology of DOX-induced cardiomyopathy [55][56][57][58]. In a model of anthracycline-induced heart failure, DOX inhibited CPC proliferation, that in combination with the accumulation of oxidative DNA damage, growth arrest, cellular senescence and apoptosis led to an almost complete depletion of the CPC pool.…”

Section: Cardiac Progenitor Cellsmentioning

confidence: 99%

Doxorubicin cardiotoxicity and target cells: a broader perspective

et al. 2016

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The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of undifferentiated cells are involved in myocardial homeostasis. Such perspective may shed light on previously unrecognized aspects of cardiotoxicity and promote new experimental and clinical cardioprotective strategies. In this review, different cellular targets of doxorubicin are discussed with the focus on cardiac progenitor cells, oxidative stress, DNA damage, senescence and apoptosis all of which contribute to their compromised functional properties.

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SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells

Cited by 68 publications

References 77 publications

New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

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

Doxorubicin cardiotoxicity and target cells: a broader perspective

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SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells

Cited by 68 publications

References 77 publications

New Role of Adult Lung c-kit+Cells in a Mouse Model of Airway Hyperresponsiveness

New Role of Adult Lung c-kit+Cells in a Mouse Model of Airway Hyperresponsiveness

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

Doxorubicin cardiotoxicity and target cells: a broader perspective

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Product

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New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness