Publications by authors named "Donato Cappetta"

35 Publications

Colchicine in ischemic heart disease: the good, the bad and the ugly.

Clin Res Cardiol 2021 Mar 13. Epub 2021 Mar 13.

Dipartimento Di Scienze Cardiovascolari E Toraciche, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A.Gemelli 8, Rome, 00168, Italy.

Inflammation is the main pathophysiological process involved in atherosclerotic plaque formation, progression, instability, and healing during the evolution of coronary artery disease (CAD). The use of colchicine, a drug used for decades in non-ischemic cardiovascular (CV) diseases and/or systemic inflammatory conditions, stimulated new perspectives on its potential application in patients with CAD. Previous mechanistic and preclinical studies revealed anti-inflammatory and immunomodulatory effects of colchicine exerted through its principal mechanism of microtubule polymerization inhibition, however, other pleiotropic effects beneficial to the CV system were observed such as inhibition of platelet aggregation and suppression of endothelial proliferation. In randomized double-blinded clinical trials informing our clinical practice, low doses of colchicine were associated with the significant reduction of cardiovascular events in patients with stable CAD and chronic coronary syndrome (CCS) while in patients with a recent acute coronary syndrome (ACS), early initiation of colchicine treatment significantly reduced major adverse CV events (MACE). On the other hand, the safety profile of colchicine and its potential causal relationship to the observed increase in non-CV deaths warrants further investigation. For these reasons, postulates of precision medicine and patient-tailored approach with regards to benefits and harms of colchicine treatment should be employed at all times due to potential toxicity of colchicine as well as the currently unresolved signal of harm concerning non-CV mortality. The main goal of this review is to provide a balanced, critical, and comprehensive evaluation of currently available evidence with respect to colchicine use in the setting of CAD.
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http://dx.doi.org/10.1007/s00392-021-01828-9DOI Listing
March 2021

Deficit of glucocorticoid-induced leucine zipper amplifies angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction.

J Cell Mol Med 2021 Jan 28;25(1):217-228. Epub 2020 Nov 28.

Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy.

Poor prognosis in heart failure and the lack of real breakthrough strategies validate targeting myocardial remodelling and the intracellular signalling involved in this process. So far, there are no effective strategies to counteract hypertrophy, an independent predictor of heart failure progression and death. Glucocorticoid-induced leucine zipper (GILZ) is involved in inflammatory signalling, but its role in cardiac biology is unknown. Using GILZ-knockout (KO) mice and an experimental model of hypertrophy and diastolic dysfunction, we addressed the role of GILZ in adverse myocardial remodelling. Infusion of angiotensin II (Ang II) resulted in myocardial dysfunction, inflammation, apoptosis, fibrosis, capillary rarefaction and hypertrophy. Interestingly, GILZ-KO showed more evident diastolic dysfunction and aggravated hypertrophic response compared with WT after Ang II administration. Both cardiomyocyte and left ventricular hypertrophy were more pronounced in GILZ-KO mice. On the other hand, Ang II-induced inflammatory and fibrotic phenomena, cell death and reduction in microvascular density, remained invariant between the WT and KO groups. The analysis of regulators of hypertrophic response, GATA4 and FoxP3, demonstrated an up-regulation in WT mice infused with Ang II; conversely, such an increase did not occur in GILZ-KO hearts. These data on myocardial response to Ang II in mice lacking GILZ indicate that this protein is a new element that can be mechanistically involved in cardiovascular pathology.
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http://dx.doi.org/10.1111/jcmm.15913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810940PMC
January 2021

Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells.

Int J Mol Sci 2020 Oct 26;21(21). Epub 2020 Oct 26.

Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kit/Gata4 CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.
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http://dx.doi.org/10.3390/ijms21217927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663580PMC
October 2020

Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity.

Sci Rep 2020 07 23;10(1):12250. Epub 2020 Jul 23.

Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138, Naples, Italy.

Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeutic modulation of microRNA expression is emerging as a cardioprotective approach in several cardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclines and is involved in cardiac repair. In our previous study, we demonstrated beneficial effects of miR-34a silencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluate the potential cardioprotective properties of a specific antimiR-34a (Ant34a) in an experimental model of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administration of Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXO-induced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients.
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http://dx.doi.org/10.1038/s41598-020-69038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378226PMC
July 2020

Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium.

Pharmacol Res 2020 07 28;157:104781. Epub 2020 Apr 28.

Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy.

The results of trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors raised the possibility that this class of drugs provides cardiovascular benefits independently from their anti-diabetic effects, although the mechanisms are unknown. Therefore, we tested the effects of SGLT2 inhibitor dapagliflozin on the progression of experimental heart disease in a non-diabetic model of heart failure with preserved ejection fraction. Dahl salt-sensitive rats were fed a high-salt diet to induce hypertension and diastolic dysfunction and were then treated with dapagliflozin for six weeks. Dapagliflozin ameliorated diastolic function as documented by echo-Doppler and heart catheterization, while blood pressure remained markedly elevated. Chronic in vivo treatment with dapagliflozin reduced diastolic Ca and Na overload and increased Ca transient amplitude in ventricular cardiomyocytes, although no direct action of dapagliflozin on isolated cardiomyocytes was observed. Dapagliflozin reversed endothelial activation and endothelial nitric oxide synthase deficit, with reduced cardiac inflammation and consequent attenuation of pro-fibrotic signaling. The potential involvement of coronary endothelium was supported by the endothelial upregulation of Na/H exchanger 1in vivo and direct effects on dapagliflozin on the activity of this exchanger in endothelial cells in vitro. In conclusions, several mechanisms may cumulatively play a significant role in the dapagliflozin-associated cardioprotection. Dapagliflozin ameliorates diastolic function and exerts a positive effect on the myocardium, possibly targeting coronary endothelium. The lower degree of endothelial dysfunction, inflammation and fibrosis translate into improved myocardial performance.
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http://dx.doi.org/10.1016/j.phrs.2020.104781DOI Listing
July 2020

VEGFR endocytosis regulates the angiogenesis in a mouse model of hindlimb ischemia.

J Thorac Dis 2019 May;11(5):1849-1859

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Background: The regulation of angiogenesis in the treatment of cardiovascular diseases has been widely studied and the vascular endothelial growth factor (VEGF) families and VEGF receptor (VEGFR) have been proven to be one of the key regulators. The VEGFR endocytosis has been recently proved to be involved in the regulation of angiogenesis. Our previous study showed that the upregulation of VEGFR endocytosis enhanced angiogenesis . In this research, we utilized mice with induced hindlimb ischemia, as a model to investigate the role of VEGFR endocytosis in the regulation of angiogenesis . Our goal was to observe the effect of revascularization with different degrees of VEGFR endocytosis after injecting atypical protein kinase C inhibitor (αPKCi) and dynasore, which could respectively promote and inhibit the VEGFR endocytosis.

Methods: We induced the hindlimb ischemia in adult male mice by ligating the hindlimb artery. By directly injecting the ischemic muscles with endothelial progenitor cells (EPCs) alone or EPCs + αPKCi/EPCs + dynasore or control medium (sham group), we divided the mice into four groups and detected lower limb blood flow using a laser Doppler blood perfusion imager. We also measured the immunohistochemistry (IHC) of markers for angiogenesis, such as CD31 and alpha smooth muscle actin (α-SMA) in the ischemic hindlimb tissues.

Results: We demonstrated VEGFR endocytosis played an important role in the angiogenesis of the ischemic hindlimb model . By using atypical PKC inhibitor that increase the VEGFR endocytosis, the angiogenesis in the mice model was promoted. Treatment with EPCs + αPKCi showed greater effects on blood perfusion recovery and increased the α-SMA-positive vessels.

Conclusions: The regulation of VEGFR endocytosis represents a valuable method of improving angiogenesis and thus revascularization in ischemic disease model.
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http://dx.doi.org/10.21037/jtd.2019.05.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588764PMC
May 2019

c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration.

Cell Death Dis 2019 06 4;10(6):436. Epub 2019 Jun 4.

Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, 88100, Italy.

An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kit stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kit knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitKIs severely affects CSCs myogenic potential. c-kitKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.
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http://dx.doi.org/10.1038/s41419-019-1655-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547756PMC
June 2019

Dipeptidyl Peptidase 4 Inhibition Ameliorates Chronic Kidney Disease in a Model of Salt-Dependent Hypertension.

Oxid Med Cell Longev 2019 10;2019:8912768. Epub 2019 Jan 10.

Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Cardiovascular diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF-B, TNF, IL-1, IL-6, and MCP-1. Kidney macrophages expressed GLP-1R, and DPP4 inhibition promoted macrophage polarization toward the anti-inflammatory M2 phenotype. Finally, high degrees of NADPH oxidase 4 expression and oxidation of nucleic acids, lipids, and proteins were reduced upon DPP4 inhibition. Our study provides evidence of renoprotection by DPP4 inhibition in a nondiabetic hypertension-induced model of chronic cardiorenal syndrome, indicating that DPP4 pathway remains a valid object to study in the context of chronic multiorgan diseases.
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http://dx.doi.org/10.1155/2019/8912768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350609PMC
March 2019

Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema.

Stem Cells Int 2018 14;2018:9492038. Epub 2018 Mar 14.

Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.

Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.
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http://dx.doi.org/10.1155/2018/9492038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872595PMC
March 2018

Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation.

Sci Rep 2018 02 13;8(1):2961. Epub 2018 Feb 13.

Department of Movement Sciences and Wellbeing, University of Naples "Parthenope", Via Medina 40, 80133, Naples, Italy.

Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD-dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53, γH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis.
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http://dx.doi.org/10.1038/s41598-018-21076-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811609PMC
February 2018

Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity.

Oxid Med Cell Longev 2017 18;2017:1521020. Epub 2017 Oct 18.

Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy.

The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.
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http://dx.doi.org/10.1155/2017/1521020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664340PMC
July 2018

Imatinib mesylate-induced cardiomyopathy involves resident cardiac progenitors.

Pharmacol Res 2018 01 28;127:15-25. Epub 2017 Sep 28.

Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address:

Cardiovascular complications are included among the systemic effects of tyrosine kinase inhibitor (TKI)-based therapeutic strategies. To test the hypothesis that inhibition of Kit tyrosine kinase that promotes cardiac progenitor cell (CPC) survival and function may be one of the triggering mechanisms of imatinib mesylate (IM)-related cardiovascular effects, the anatomical, structural and ultrastructural changes in the heart of IM-treated rats were evaluated. Cardiac anatomy in IM-exposed rats showed a dose-dependent, restrictive type of remodeling and depressed hemodynamic performance in the absence of remarkable myocardial fibrosis. The effects of IM on rat and human CPCs were also assessed. IM induced rat CPC depletion, reduced growth and increased cell death. Similar effects were observed in CPCs isolated from human hearts. These results extend the notion that cardiovascular side effects are driven by multiple actions of IM. The identification of cellular mechanisms responsible for cardiovascular complications due to TKIs will enable future strategies aimed at preserving concomitantly cardiac integrity and anti-tumor activity of advanced cancer treatment.
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http://dx.doi.org/10.1016/j.phrs.2017.09.020DOI Listing
January 2018

Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies.

Int J Cardiol 2017 Aug 1;241:330-343. Epub 2017 Mar 1.

Department of Cardiovascular Medicine, Catholic University of the Sacred Heart, Rome, Italy. Electronic address:

Aims: In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate.

Methods And Results: EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4±0.4kbp and telomerase activity was present in all preparations (1.7×10 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance.

Conclusions: The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.106DOI Listing
August 2017

Doxorubicin targets multiple players: A new view of an old problem.

Pharmacol Res 2018 01 20;127:4-14. Epub 2017 Mar 20.

Department of Experimental Medicine, Section of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy. Electronic address:

Anthracycline cardiotoxicity remains a serious problem in paediatric and adult cancer survivors, and the advancement of cardio-oncology is a necessary step for an effective care of the patients that experience adverse cardiovascular effects. In this review, we discuss the multiple instruments used by clinicians that constitute the current strategies for primary and secondary prevention aiming at contrasting the onset of early and late doxorubicin-induced cardiotoxic events. The importance of early detection of cardiotoxicity and the following pharmacological therapy has been acknowledged with the emphasis put on impaired diastolic function, an increasingly recognized precocious sign of doxorubicin cardiotoxicity with an emerging scientific and clinical interest. We highlight the involvement of progenitor cells of cardiac and extra-cardiac origin as well as multiple cardiac cell types (fibroblasts and vasculature cells), focusing on molecular signals involved in cellular injury and response. Oxidative stress, DNA damage, senescence and cell death are established mechanisms driving anthracycline toxicity, but the comprehension of their relative weight on affecting specific cell type behaviour remains to be consolidated. The contribution of these crucial stressors and the emerging tools for preserving cell function are discussed.
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http://dx.doi.org/10.1016/j.phrs.2017.03.016DOI Listing
January 2018

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

Br J Pharmacol 2017 Nov 16;174(21):3696-3712. Epub 2017 May 16.

Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background And Purpose: 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 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 Approach: Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg , daily) for the following 4 weeks.

Key Results: While 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 exchanger 1 and Na 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis.

Conclusions And Implications: Ranolazine, by the increased Na influx, induced by doxorubicin, altered cardiac Ca and Na handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy.

Linked Articles: This 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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http://dx.doi.org/10.1111/bph.13791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647186PMC
November 2017

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

Mediators Inflamm 2016 20;2016:3917471. Epub 2016 Dec 20.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, 80138 Naples, Italy.

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 TGF 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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http://dx.doi.org/10.1155/2016/3917471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206449PMC
August 2017

Sitagliptin reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction.

Br J Pharmacol 2017 Nov 21;174(22):4070-4086. Epub 2017 Mar 21.

Department of Experimental Medicine, Section of Pharmacology, Univesity of Campania "Luigi Vanvitelli", Naples, Italy.

Background And Purpose: Heart failure with preserved ejection fraction (HFpEF) is a systemic syndrome driven by co-morbidities, and its pathophysiology is poorly understood. Several studies suggesting that dipeptidyl peptidase 4 (DPP4) might be involved in the pathophysiology of heart failure have prompted experimental and clinical investigations of DPP4 inhibitors in the cardiovascular system. Here we have investigated whether the DPP4 inhibitor sitagliptin affected the progression of HFpEF independently of its effects on glycaemia.

Experimental Approach: Seven-week-old Dahl salt-sensitive rats were fed a high-salt diet for 5 weeks to induce hypertension. Then the rats continued with the high-salt diet and were treated with either sitagliptin (10 mg·kg ) or vehicle for the following 8 weeks. Blood pressure and cardiac function were measured in vivo. Histochemical and molecular biology analyses of myocardium were used to assay cytokines, fibrotic markers, DPP4 and glucagon-like peptide-1 (GLP-1)/GLP-1 receptor.

Key Results: Treatment with sitagliptin attenuated diastolic dysfunction, reduced mortality and reduced cardiac DPP4 activity, along with increased circulating GLP-1 and myocardial expression of GLP-1 receptors. Myocardial levels of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) were reduced. Sitagliptin treatment decreased the levels of endothelial NOS monomer, responsible for generation of ROS, while the amount of NO-producing dimeric form increased. Markers of oxidative and nitrosative stress were decreased. Moreover, increased collagen deposition and activation of pro-fibrotic signalling, inducing elevated myocardial stiffness, were attenuated by sitagliptin treatment.

Conclusions And Implications: Sitagliptin positively modulated active relaxation and passive diastolic compliance by decreasing inflammation-related endothelial dysfunction and fibrosis, associated with HFpEF.

Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
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http://dx.doi.org/10.1111/bph.13686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659996PMC
November 2017

MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat.

Oncotarget 2016 Sep;7(38):62312-62326

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.

New strategies to prevent and early detect the cardiotoxic effects of the anticancer drug doxorubicin (DOXO) are required. MicroRNAs emerged as potential diagnostic, therapeutic and prognostic approaches in cardiovascular diseases. MiR-34a has a role in cardiac dysfunction and ageing and is involved in several cellular processes associated with DOXO cardiotoxicity. Our in vitro and in vivo results indicated that after DOXO exposure the levels of miR-34a are enhanced in cardiac cells, including Cardiac Progenitor Cells (CPCs). Since one of the determining event responsible for the initiation and evolution of the DOXO toxicity arises at the level of the CPC compartment, we evaluated if miR-34a pharmacological inhibition in these cells ameliorates the detrimental aftermath of the drug. AntimiR-34a has beneficial consequences on vitality, proliferation, apoptosis and senescence of DOXO-treated rat CPC. These effects are mediated by an increase of prosurvival miR-34a targets Bcl-2 and SIRT1, accompanied by a decrease of acetylated-p53 and p16INK4a. Importantly, miR-34a silencing also reduces the release of this miRNA from DOXO-exposed rCPCs, decreasing its negative paracrine effects on other rat cardiac cells. In conclusion, the silencing of miR-34a could represent a future therapeutic option for cardioprotection in DOXO toxicity and at the same time, it could be considered as a circulating biomarker for anthracycline-induced cardiac damage.
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http://dx.doi.org/10.18632/oncotarget.11468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308729PMC
September 2016

Intratracheal Administration of Mesenchymal Stem Cells Modulates Tachykinin System, Suppresses Airway Remodeling and Reduces Airway Hyperresponsiveness in an Animal Model.

PLoS One 2016 19;11(7):e0158746. Epub 2016 Jul 19.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.

Background: The need for new options for chronic lung diseases promotes the research on stem cells for lung repair. Bone marrow-derived mesenchymal stem cells (MSCs) can modulate lung inflammation, but the data on cellular processes involved in early airway remodeling and the potential involvement of neuropeptides are scarce.

Objectives: To elucidate the mechanisms by which local administration of MSCs interferes with pathophysiological features of airway hyperresponsiveness in an animal model.

Methods: GFP-tagged mouse MSCs were intratracheally delivered in the ovalbumin mouse model with subsequent functional tests, the analysis of cytokine levels, neuropeptide expression and histological evaluation of MSCs fate and airway pathology. Additionally, MSCs were exposed to pro-inflammatory factors in vitro.

Results: Functional improvement was observed after MSC administration. Although MSCs did not adopt lung cell phenotypes, cell therapy positively affected airway remodeling reducing the hyperplastic phase of the gain in bronchial smooth muscle mass, decreasing the proliferation of epithelium in which mucus metaplasia was also lowered. Decrease of interleukin-4, interleukin-5, interleukin-13 and increase of interleukin-10 in bronchoalveolar lavage was also observed. Exposed to pro-inflammatory cytokines, MSCs upregulated indoleamine 2,3-dioxygenase. Moreover, asthma-related in vivo upregulation of pro-inflammatory neurokinin 1 and neurokinin 2 receptors was counteracted by MSCs that also determined a partial restoration of VIP, a neuropeptide with anti-inflammatory properties.

Conclusion: Intratracheally administered MSCs positively modulate airway remodeling, reduce inflammation and improve function, demonstrating their ability to promote tissue homeostasis in the course of experimental allergic asthma. Because of a limited tissue retention, the functional impact of MSCs may be attributed to their immunomodulatory response combined with the interference of neuropeptide system activation and tissue remodeling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158746PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951036PMC
July 2017

Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction.

Int J Cardiol 2016 Aug 12;217:69-79. Epub 2016 May 12.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.

Background: To investigate the effects of chronic administration of ranolazine (RAN) on experimental model of heart failure with preserved ejection fraction.

Methods: Seven-weeks old Dahl salt-sensitive rats were fed a high salt diet for 5weeks to induce hypertension. Afterwards, rats continued with a high salt diet and were administered either with vehicle or RAN (20mg/kg/die, ip) for the following 8weeks. Control rats were maintained on a low salt diet.

Results: While systolic parameters were not altered, diastolic parameters were changed in high salt animals. Hemodynamic analysis showed a decreased dP/dt min, increased LVEDP, longer time constant and steeper slope of the end-diastolic pressure-volume relationship. Treatment with RAN attenuated these alterations and determined a reduction in mortality. Additionally, the magnitude of myocardial hypertrophy and activation of PI3K/Akt pathway were reduced. Alteration in diastolic compliance as a consequence of elevated myocardial stiffness was confirmed by an increase of collagen deposition and activation of pro-fibrotic TGF-β/SMAD3/CTGF signaling. These effects were counteracted by RAN. High salt rats had a decrease in SERCA2 and an increase in Na(+)/Ca(2+) exchanger (NCX). Treatment with RAN reduced NCX expression and determined an increment of SERCA2. Moreover, the levels of nitrotyrosine and oxidized dyhydroethidium were higher in high salt rats. RAN induced a decrement of oxidative stress, supporting the concept that reduction in ROS may mediate beneficial effects.

Conclusions: Our findings support the possibility that diastolic dysfunction can be attenuated by RAN, indicating its ability to affect active relaxation and passive diastolic compliance.
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http://dx.doi.org/10.1016/j.ijcard.2016.04.168DOI Listing
August 2016

Mechanical Stress Regulates Endothelial Progenitor Cell Angiogenesis Through VEGF Receptor Endocytosis.

Int Heart J 2016 May 28;57(3):356-62. Epub 2016 Apr 28.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University.

The clinical goal of cell-based treatment for chronic heart failure is to coordinately reconstitute the cardiomyocytes and associated circulation environment including coronary resistance arteries, arterioles, and capillary profiles.(1)) This goal can be possibly achieved by implementing multipotent adult stem cells. However, it remains a challenge to modify the capillary network in the decompensated heart. A mechanical stress model was used in this study to mimic the hemodynamic and hormonal states of the decompensated heart in vitro. The angiogenesis role of endothelial progenitor cells (EPCs) under stress has been well-recognized in vascular repair. We investigated the molecular mechanisms of EPCs in this model. We found that expression of vascular endothelial growth factor (VEGF) in EPCs was significantly decreased by mechanical stress, and this effect was accompanied by a decrease in angiogenesis in vitro. Interestingly, the defective angiogenesis can be reversed by upregulating the membrane VEGF receptor (VEGFR) endocytosis. An atypical protein kinase C (aPKC) inhibitor can promote the VEGFR internalization in EPCs and enhance the formation of vascular networks. Thus, the upregulation of VEGFR endocytosis in EPCs could be a potential therapy for the cell-based treatment of chronic heart failure by enhancing the cardiomyocytes.
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http://dx.doi.org/10.1536/ihj.15-387DOI Listing
May 2016

Doxorubicin cardiotoxicity and target cells: a broader perspective.

Cardiooncology 2016 Mar 3;2(1). Epub 2016 Mar 3.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, via Costantinopoli 16, 80138, Naples, Italy.

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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http://dx.doi.org/10.1186/s40959-016-0012-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837148PMC
March 2016

SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy.

Int J Cardiol 2016 Feb 15;205:99-110. Epub 2015 Dec 15.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.

Background: Doxorubicin (DOXO) is an effective anti-neoplastic drug but its clinical benefits are hampered by cardiotoxicity. Oxidative stress, apoptosis and myocardial fibrosis mediate the anthracycline cardiomyopathy. ROS trigger TGF-β pathway that activates cardiac fibroblasts promoting fibrosis. Myocardial stiffness contributes to diastolic dysfunction, less studied aspect of anthracycline cardiomyopathy. Considering the role of SIRT1 in the inhibition of the TGF-β/SMAD3 pathway, resveratrol (RES), a SIRT1 activator, might improve cardiac function by interfering with the development of cardiac fibrosis in a model of DOXO-induced cardiomyopathy.

Methods: F344 rats received a cumulative dose of 15 mg/kg of DOXO in 2 weeks or DOXO+RES (DOXO and RES, 2.5mg/kg/day, concomitantly for 2 weeks and then RES alone for 1 more week). The effects of RES on cardiac fibroblasts were also tested in vitro.

Results: Along with systolic dysfunction, DOXO was also responsible of diastolic abnormalities. Myocardial stiffness correlated with fibroblast activation and collagen deposition. DOXO+RES co-treatment significantly improved ± dP/dt and, more interestingly, ameliorated end-diastolic pressure/volume relationship. Treatment with RES resulted in reduced fibrosis and fibroblast activation and, most importantly, the mortality rate was significantly reduced in DOXO+RES group. Fibroblasts isolated from DOXO+RES-treated rats, in which SIRT1 was upregulated, showed decreased levels of TGF-β and pSMAD3/SMAD3 when compared to cells isolated from DOXO-exposed hearts.

Conclusions: Our findings reveal a key role of SIRT1 in supporting animal survival and functional parameters of the heart. SIRT1 activation by interfering with fibrogenesis can improve relaxation properties of myocardium and attenuate myocardial remodeling related to chemotherapy.
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http://dx.doi.org/10.1016/j.ijcard.2015.12.008DOI Listing
February 2016

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

Int J Cardiol 2015 2;189:30-44. Epub 2015 Apr 2.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.

Background: The search for compounds able to counteract chemotherapy-induced heart failure is extremely important at the age of global cancer epidemic. The role of SIRT1 in the maintenance of progenitor cell homeostasis may contribute to its cardioprotective effects. SIRT1 activators, by preserving progenitor cells, could have a clinical relevance for the prevention of doxorubicin (DOXO)-cardiotoxicity.

Methods: To determine whether SIRT1 activator, resveratrol (RES), interferes with adverse effects of DOXO on cardiac progenitor cells (CPCs): 1) human CPCs (hCPCs) were exposed in vitro to DOXO or DOXO+RES and their regenerative potential was tested in vivo in an animal model of DOXO-induced heart failure; 2) the in vivo effects of DOXO+RES co-treatment on CPCs were studied in a rat model.

Results: In contrast to healthy cells, DOXO-exposed hCPCs were ineffective in a model of anthracycline cardiomyopathy. The in vitro activation of SIRT1 decreased p53 acetylation, overcame suppression of the IGF-1/Akt pro-survival and anti-apoptotic signaling, enhanced oxidative stress defense and prevented senescence and growth arrest of hCPCs. Priming with RES counterbalanced the onset of dysfunctional phenotype in DOXO-exposed hCPCs, partly restoring their ability to repair the damage with improvement in cardiac function and animal survival. The in vivo co-treatment DOXO+RES prevented the anthracycline-induced alterations in CPCs, partly preserving cardiac function.

Conclusion: SIRT1 activation protects DOXO-exposed CPCs and re-establishes their proper function. Pharmacological intervention at the level of tissue-specific progenitor cells may provide cardiac benefits for the growing population of long-term cancer survivors that are at risk of chemotherapy-induced cardiovascular toxicity.
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http://dx.doi.org/10.1016/j.ijcard.2015.03.438DOI Listing
April 2016

Recumbent deoxygenation in mild/moderate liver cirrhosis: the "clinodeoxia". The ortho-clino paradigm.

Respir Med 2014 Jul 15;108(7):1040-8. Epub 2014 Apr 15.

Meakins-Christie Laboratories, McGill University, Montreal, PQ, Canada.

Background: While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). We evaluated the effects of postural changes on arterial oxygenation in patients affected by mild/moderate liver cirrhosis.

Methods: We performed pulmonary function tests and arterial blood gas evaluation in sitting and supine positions in 22 patients with mild/moderate liver cirrhosis, biopsy-proved, and 22 matched non-smokers control subjects.

Results: Recumbency elicited a decrease of PaO2 (Δ(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p = 0.04) greater in cirrhotics (9.6 ± 5.3%) compared to controls (6.7 ± 3.7%). In the subset of cirrhotics younger than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Δ(sup-sit)PaO2 in recumbency further increased to 12 ± 5.8%, significantly (p = 0.014) greater than in same subgroup of controls (7.1 ± 3.8%).

Conclusions: In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia").
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http://dx.doi.org/10.1016/j.rmed.2014.04.003DOI Listing
July 2014

c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy.

Circ Res 2014 Jan 29;114(1):41-55. Epub 2013 Oct 29.

From the Departments of Anesthesia (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.) and Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., E.I., M.A.P., P.G., J.K., T.H., M. Rota, P.A., A.L.), and Divisions of Cardiovascular Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.), Pulmonary and Critical Care Medicine (E.I., M.A.P., A.M.C.), and Newborn Medicine (M.A.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Rationale: Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown.

Objective: A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal.

Methods And Results: Here, we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot re-enter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy.

Conclusions: Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy.
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http://dx.doi.org/10.1161/CIRCRESAHA.114.302500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959163PMC
January 2014

C-reactive protein and carotid intima-media thickness in children with sleep disordered breathing.

J Clin Sleep Med 2013 May 15;9(5):493-8. Epub 2013 May 15.

Department of Internal Medicine, A. Cardarelli Hospital, Naples, Italy.

Study Objectives: Obesity is a risk factor for sleep disordered breathing (SDB) in children. Plasma levels of high-sensitivity C-reactive protein (Hs-CRP) are predictive of cardiovascular morbidity in adults, and CRP levels are associated with over-weight. Increased carotid intima-media thickness (IMT) is associated with several cardiovascular risk factors. We evaluated the effect of SDB on CRP levels and IMT in lean and obese children not selected for snoring.

Methods: 101 children (age 5-15 years) attending a weight clinic or scheduled for routine visit. IMT was measured with quantitative B-mode ultrasound scans. The apnea-hypopnea index (AHI) was measured overnight: AHI < 1 defined controls, AHI ≥ 1 to < 5 = mild SDB, and AHI ≥ 5 = obstructive sleep apnea (OSA).

Results: AHI was significantly associated with Hs-CRP concentration (r = 0.32, p = 0.002) in all 101 children irrespective of age and sex. Body mass index (BMI) was higher in OSA children than controls (25.5 ± 7.0 vs 22.1 ± 6.9, p = 0.05). Obese children had 3.3 times more probability of having OSA (HR 3.3, 95% CI 1.2-9.3, p = 0.02) than lean children. Hs-CRP values were significantly higher in children with OSA than in children without (p = 0.011), but not when BMI z-score was added as covariate. IMT was not associated with AHI or SDB.

Conclusions: The results of this study suggest an association between OSA and Hs-CRP concentrations (mainly mediated by overweight and obesity), but not between OSA and subclinical atherosclerosis. There is scope for prevention in childhood before OSA syndrome causes the irreversible damage to arteries observed in adult patients.
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http://dx.doi.org/10.5664/jcsm.2674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629324PMC
May 2013

Doxorubicin induces senescence and impairs function of human cardiac progenitor cells.

Basic Res Cardiol 2013 Mar 15;108(2):334. Epub 2013 Feb 15.

Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.

The increasing population of cancer survivors faces considerable morbidity and mortality due to late effects of the antineoplastic therapy. Cardiotoxicity is a major limiting factor of therapy with doxorubicin (DOXO), the most effective anthracycline, and is characterized by a dilated cardiomyopathy that can develop even years after treatment. Studies in animals have proposed the cardiac progenitor cells (CPCs) as the cellular target responsible for DOXO-induced cardiomyopathy but the relevance of these observations to clinical settings is unknown. In this study, the analysis of the DOXO-induced cardiomyopathic human hearts showed that the majority of human CPCs (hCPCs) was senescent. In isolated hCPCs, DOXO triggered DNA damage response leading to apoptosis early after exposure, and telomere shortening and senescence at later time interval. Functional properties of hCPCs, such as migration and differentiation, were also negatively affected. Importantly, the differentiated progeny of DOXO-treated hCPCs prematurely expressed the senescence marker p16(INK4a). In conclusion, DOXO exposure severely affects the population of hCPCs and permanently impairs their function. Premature senescence of hCPCs and their progeny can be responsible for the decline in the regenerative capacity of the heart and may represent the cellular basis of DOXO-induced cardiomyopathy in humans.
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http://dx.doi.org/10.1007/s00395-013-0334-4DOI Listing
March 2013

Cardiomyogenesis in the aging and failing human heart.

Circulation 2012 Oct 6;126(15):1869-81. Epub 2012 Sep 6.

Department of Anesthesia, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Background: Two opposite views of cardiac growth are currently held; one views the heart as a static organ characterized by a large number of cardiomyocytes that are present at birth and live as long as the organism, and the other views the heart a highly plastic organ in which the myocyte compartment is restored several times during the course of life.

Methods And Results: The average age of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover rates were measured by retrospective (14)C birth dating of cells in 19 normal hearts 2 to 78 years of age and in 17 explanted failing hearts 22 to 70 years of age. We report that the human heart is characterized by a significant turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth, decreases during postnatal maturation, remains relatively constant in the adult organ, and increases dramatically with age. From 20 to 78 years of age, the adult human heart entirely replaces its myocyte, EC, and fibroblast compartment ≈8, ≈6, and ≈8 times, respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic heart failure.

Conclusions: The human heart is a highly dynamic organ that retains a remarkable degree of plasticity throughout life and in the presence of chronic heart failure. However, the ability to regenerate cardiomyocytes, vascular ECs, and fibroblasts cannot prevent the manifestations of myocardial aging or oppose the negative effects of ischemic and idiopathic dilated cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.118380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477474PMC
October 2012

Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium.

Circ Res 2012 Sep 31;111(7):894-906. Epub 2012 Jul 31.

Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Rationale: According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening.

Objective: Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration.

Methods And Results: Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal and long-term repopulating ability of these cells was shown in serial-transplantation assays in the infarcted heart; these cells created a chimeric organ, composed of spared rat and regenerated human cardiomyocytes and coronary vessels, leading to a remarkable restoration of cardiac structure and function. The documentation that hCSCs divide by asymmetrical and symmetrical chromatid segregation supports the view that the human heart is a self-renewing organ regulated by a compartment of resident hCSCs.

Conclusions: The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell class for the management of heart failure in humans.
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http://dx.doi.org/10.1161/CIRCRESAHA.112.273649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482833PMC
September 2012