Doxorubicin induces senescence and impairs function of human cardiac progenitor cells

Piegari, Elena; Angelis, Antonella De; Cappetta, Donato; Russo, Rosa; Esposito, Grazia; Costantino, Sarah; Graiani, Gallia; Frati, Caterina; Prezioso, Lucia; Berrino, Liberato; Urbanek, Konrad; Quaini, Federico; Rossi, Francesco

doi:10.1007/s00395-013-0334-4

Cited by 140 publications

(143 citation statements)

References 60 publications

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“…It has been assumed that the loss of a chemokine/GF gradient within the healed myocardium may be responsible for the lack of endogenous repair despite an actual increase of tissue CPCs (58,64,82). Our results on BrdU incorporation and Ki-67 labeling support the contention that more robust myocardial regeneration, compared with untreated MI, can be obtained via all three regenerative therapies, which may reverse the unfavorable microenvironment and promote the repairing ability of CPCs either resident or locally injected.…”

Section: Cardiac Regeneration Anatomy and Mechanicssupporting

confidence: 71%

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Savi

Bocchi

Rossi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Kit pos cardiac progenitor cells (CPCs) represent a successful approach in healing the infarcted heart and rescuing its mechanical function, but electrophysiological consequences are uncertain. CPC mobilization promoted by hepatocyte growth factor (HGF) and IGF-1 improved electrogenesis in myocardial infarction (MI). We hypothesized that locally delivered CPCs supplemented with HGF ϩ IGF-1 (GFs) can concur in ameliorating electrical stability of the regenerated heart. Adult male Wistar rats (139 rats) with 4-wk-old MI or sham conditions were randomized to receive intramyocardial injection of GFs, CPCs, CPCs ϩ GFs, or vehicle (V). Enhanced green fluorescent protein-tagged CPCs were used for cell tracking. Vulnerability to stress-induced arrhythmia was assessed by telemetry-ECG. Basic cardiac electrophysiological properties were examined by epicardial multiple-lead recording. Hemodynamic function was measured invasively. Hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. Compared with V and at variance with individual CPCs, CPCs ϩ GFs approximately halved arrhythmias in all animals, restoring cardiac anisotropy toward sham values. GFs alone reduced arrhythmias by less than CPCs ϩ GFs, prolonging ventricular refractoriness without affecting conduction velocity. Concomitantly, CPCs ϩ GFs reactivated the expression levels of Connexin-43 and Connexin-40 as well as channel proteins of key depolarizing and repolarizing ion currents differently than sole GFs. Mechanical function and anatomical remodeling were equally improved by all regenerative treatments, thus exhibiting a divergent behavior relative to electrical aspects. Conclusively, we provided evidence of distinctive antiarrhythmic action of locally injected GF-supplemented CPCs, likely attributable to retrieval of Connexin-43, Connexin-40, and Cav1.2 expression, favoring intercellular coupling and spread of excitation in mended heart. cardiac progenitor cells; growth factors and cytokines; myocardial infarction; arrhythmia; cardiac gap junction connexins NEW & NOTEWORTHY Repair of infarcted heart by local injection of c-kit pos cardiac progenitors supplemented with hepatocyte growth factor and IGF-1 has distinctive antiarrhythmic effects involving recovery of Connexin-43, Connexin-40, and Ca v1.2 expression levels differently than progenitors or cytokines alone. This new insight into the impact of regenerative therapies on cardiac electrogenesis has clinical relevance.HEART FAILURE (HF) very often proceeds as a consequence of myocardial infarction (MI) (59) and continues to be a major health problem (49). Over the past 15 yr, cell therapy has emerged as a new strategy aimed at revitalizing dead myocardium, thus circumventing the unfavorable outcome of degenerative heart diseases, including the vicious circle of MI/HF (67). However, results obtained so far in clinical trials with a large sample size using cells of different origin, mainly skeletal myoblasts (44) and bone marrow cells (78), have been contradictor...

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Section: Cardiac Regeneration Anatomy and Mechanicssupporting

confidence: 71%

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Savi

Bocchi

Rossi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…This has been intensified by recognition that Mfn2 may play a critical role in cell‐based therapies promoting the differentiation of stem cells into cardiomyocytes (Kasahara et al, 2013; Suliman et al, 2016). Indeed, DOX‐induced cardiomyopathy is associated with depletion and senescence of the cardiac progenitor cell pool in both rat and human hearts, permanently impairing their function (de Angelis et al, 2010; Piegari et al, 2013). Therefore, a pharmacological strategy involving Mfn2 that could potentially prevent degeneration of both adult cardiac cells and the resident stem cell pool seems an attractive idea.…”

Section: Discussionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…In a juvenile mouse model treated with DOX, the development of an abnormal vasculature resulted in higher susceptibility to myocardial infarction. Also, a decreased number of CPCs was observed after DOX treatment, suggesting that these undifferentiated cells are more susceptible to DOX, thus limiting the resistance of the treated heart to oxidative stress [9,59]. According to this, Angelis et al reported also that adult and neonatal rat cardiomyocytes have different susceptibilities to DOX exposure, with the apoptotic pathway being more active in immature cells [60].…”

Section: Discussionmentioning

confidence: 97%

“…CPCs have been studied in the context of several pathological conditions in animal and humans including as a pathophysiological target against DOX cardiotoxicity [9][10][11][12]. One relevant model to investigate DOXinduced effects on CPCs is the H9c2 cell line, which has morphological characteristics similar to immature embryonic cardiomyocytes [2,[13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

“…Adult cardiac progenitor cells (CPCs), present in adult heart, contain stem cell characteristics and are involved in tissue homeostasis and myocardial regeneration during pathological conditions [7][8][9]. CPCs have been studied in the context of several pathological conditions in animal and humans including as a pathophysiological target against DOX cardiotoxicity [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts

Coelho

Martins

Couto

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A B S T R A C TDoxorubicin (DOX) is one of the most widely used anti-neoplastic agents. However, treatment with DOX is associated with cumulative cardiotoxicity inducing progressive cardiomyocyte death. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, regulates the activity of proteins involved in apoptosis, autophagy and metabolism. Our hypothesis is that pharmacological modulation by berberine (BER) pre-conditioning of Sirt3 protein levels decreases DOX-induced cardiotoxicity. Our results showed that DOX induces cell death in all experimental groups. Increase in Sirt3 content by transfection-mediated overexpression decreased DOX cytotoxicity, mostly by maintaining mitochondrial network integrity and reducing oxidative stress. p53 was upregulated by DOX, and appeared to be a direct target of Sirt3, suggesting that Sirt3-mediated protection against cell death could be related to this protein. BER pre-treatment increased Sirt3 and Sirt1 protein levels in the presence of DOX and inhibited DOX-induced caspase 9 and 3-like activation. Moreover, BER modulated autophagy in DOX-treated H9c2 cardiomyoblasts. Interestingly, mitochondrial biogenesis markers were upregulated in in BER/DOX-treated cells. Sirt3 over-expression contributes to decrease DOX cytotoxicity on H9c2 cardiomyoblasts, while BER can be used as a modulator of Sirtuin function and cell quality control pathways to decrease DOX toxicity.

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Doxorubicin induces senescence and impairs function of human cardiac progenitor cells

Cited by 140 publications

References 60 publications

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Antiarrhythmic effect of growth factor-supplemented cardiac progenitor cells in chronic infarcted heart

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts

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