Maurizio C Capogrossi

Publications (156)811.91 Total impact

• Article: c-kit-Positive Cardiac Progenitor Cells: The Heart of Stemness.

  Alessandra Magenta, Daniele Avitabile, Giulio Pompilio, Maurizio C Capogrossi
  Circulation Research 04/2013; 112(9):1202-4. · 9.49 Impact Factor
• Source

  Available from: Carlo Gaetano

  Article: A Nitric Oxide-dependent Crosstalk Between Class I and III Histone Deacetylases Accelerates Skin Repair.

  Francesco Spallotta, Chiara Cencioni, Stefania Straino, Simona Nanni, Jessica Rosati, Simona Artuso, Isabella Manni, Claudia Colussi, Giulia Piaggio, Fabio Martelli, Sergio Valente, Antonello Mai, Maurizio C Capogrossi, Antonella Farsetti, Carlo Gaetano
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  ABSTRACT: In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor (DI) Trichostatin A (TSA) accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III HDACs (sirtuins) selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using Resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we recently synthesized. Both Resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via eNOS phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a posttransduction modification associated to loss of activity and DNA binding capacity. After DIs or SIRT activators treatment chromatin immunoprecipitation (ChIPs) showed, in fact, a significant HDAC2 detachment from the promoter region of Insulin Growth Factor I (IGF-I), Fibroblast Growth Factor 10 (FGF-10) and Epithelial Growth Factor (EGF) which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of L-NAME, a general inhibitor of NO synthesis. In conclusion, the NO-dependent crosstalk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.
  Journal of Biological Chemistry 03/2013; · 4.77 Impact Factor
• Article: Hypoxia/Reoxygenation cardiac injury and regeneration in zebrafish adult heart.

  Valeria Parente, Serena Balasso, Giulio Pompilio, Lorena Verduci, Gualtiero I Colombo, Giuseppina Milano, Uliano Guerrini, Lidia Squadroni, Franco Cotelli, Ombretta Pozzoli, Maurizio C Capogrossi
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  ABSTRACT: the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it. adult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL(+) and 15.0±2.5% were AO(+). At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3(+) and 7.4±0.6% were PCNA(+) (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point). zebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models.
  PLoS ONE 01/2013; 8(1):e53748. · 4.09 Impact Factor
• Article: Growth Induction and Low-Oxygen Apoptosis Inhibition of Human CD34(+) Progenitors in Collagen Gels.

  Daniele Avitabile, Katrin Salchert, Carsten Werner, Maurizio C Capogrossi, Maurizio Pesce
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  ABSTRACT: Various reports have indicated low survival of injected progenitors into unfavorable environments such as the ischemic myocardium or lower limb tissues. This represents a major bottleneck in stem-cell-based cardiovascular regenerative medicine. Strategies to enhance survival of these cells in recipient tissues have been therefore sought to improve stem cell survival and ensure long-term engraftment. In the present contribution, we show that embedding human cord blood-derived CD34(+) cells into a collagen I-based hydrogel containing cytokines is a suitable strategy to promote stem cell proliferation and protect these cells from anoxia-induced apoptosis.
  BioMed research international. 01/2013; 2013:542810.
• Source

  Available from: Carlo Gaetano

  Article: Estrogen-Dependent Dynamic Profile of eNOS-DNA Associations in Prostate Cancer.

  Simona Nanni, Aurora Aiello, Agnese Re, Alessandro Guffanti, Valentina Benvenuti, Claudia Colussi, Luis Jaime Castro-Vega, Armando Felsani, Arturo Londono-Vallejo, Maurizio C Capogrossi, Silvia Bacchetti, Carlo Gaetano, Alfredo Pontecorvi, Antonella Farsetti
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  ABSTRACT: In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5' domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa.
  PLoS ONE 01/2013; 8(5):e62522. · 4.09 Impact Factor
• Source

  Available from: Pierangela Totta

  Dataset: De Falco et al., j mol med 2008

  Elena De Falco, Daniele Avitabile, Pierangela Totta, Stefania Straino, Francesco Spallotta, Chiara Cencioni, Anna Rita Torella, Roberto Rizzi, Daniele Porcelli, Antonella Zacheo, Luca Di Vito, Giulio Pompilio, Monica Napolitano, Guido Melillo, Maurizio C Capogrossi, Maurizio Pesce
• Article: [The SCIPIO and CADUCEUS studies].

  Giulio Pompilio, Maurizio C Capogrossi, Antonio Maria Leone, Filippo Crea
  Giornale italiano di cardiologia (2006) 12/2012; 13(12):777-82.
• Article: Circulating microRNAs (miRs) for diagnosing acute myocardial infarction: An exciting challenge.

  Fabiola Olivieri, Roberto Antonicelli, Maurizio C Capogrossi, Antonio Domenico Procopio
  International journal of cardiology 11/2012; · 7.08 Impact Factor
• Article: Hypoxia Inducible Factor 1- alpha induces miR-210 in normoxic differentiating myoblasts.

  Lucia Cicchillitti, Valeria Di Stefano, Eleonora Isaia, Luca Crimaldi, Pasquale Fasanaro, Valeria Ambrosino, Annalisa Antonini, Maurizio C Capogrossi, Carlo Gaetano, Giulia Piaggio, Fabio Martelli
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  ABSTRACT: microRNA-210 (miR-210) induction is a virtually constant feature of the hypoxic response in both normal and transformed cells, regulating several key aspects of cardiovascular diseases and cancer. We found that miR-210 was induced in normoxic myoblasts upon myogenic differentiation, both in vitro and in vivo. miR-210 transcription was activated in an Hypoxia Inducible Factor 1-alpha (Hif1a) dependent manner and Chromatin Immunoprecipitation experiments show that Hif1a bound to miR-210 promoter only in differentiated myotubes. Accordingly, luciferase reporter assays demonstrated the functional relevance of Hif1a binding site for miR-210 promoter activation in differentiating myoblasts. To investigate the functional relevance of increased miR-210 levels in differentiated myofibers, we blocked miR-210 with complementary Locked Nucleic Acid oligonucleotides (anti-miR-210). We found that C2C12 myoblast cell line differentiation was largely unaffected by anti-210. Likewise, miR-210 inhibition did not affect skeletal muscle regeneration following cardiotoxin damage. However, we found that miR-210 blockade greatly increased myotube sensitivity to oxidative stress and mitochondrial dysfunction. In conclusion, miR-210 is induced in normoxic myofibers playing a cytoprotective role.
  Journal of Biological Chemistry 11/2012; · 4.77 Impact Factor
• Source

  Available from: Carlo Gaetano

  Article: P300/CBP Associated Factor Regulates Nitroglycerin-Dependent Arterial Relaxation by N{varepsilon}-Lysine Acetylation of Contractile Proteins.

  Claudia Colussi, Alessandro Scopece, Serena Vitale, Francesco Spallotta, Stefania Mattiussi, Jessica Rosati, Barbara Illi, Antonello Mai, Sabrina Castellano, Gianluca Sbardella, Antonella Farsetti, Maurizio C Capogrossi, Carlo Gaetano
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  ABSTRACT: To address the role of epigenetic enzymes in the process of arterial vasorelaxation and nitrate tolerance, in vitro and in vivo experiments were performed in the presence or absence of glyceryl trinitrate (GTN) or histone deacetylases/histone acetylases modulators. In vitro single GTN administration rapidly increased cGMP synthesis and protein N(ε)-lysine acetylation in rat smooth muscle cells, including myosin light chain and smooth muscle actin. This phenomenon determined a decrease in myosin light chain phosphorylation and actomyosin formation. These effects were abolished by prolonged exposure to GTN and rescued by treatment with trichostatin A. In vivo, adult male rats were treated for 72 hours with subcutaneous injections of GTN alone or in combination with the histone deacetylases inhibitors trichostatin A, suberoylanilide hydroxamic acid, MS-27-275, or valproic acid. Ex vivo experiments performed on aortic rings showed that the effect of tolerance was reversed by all proacetylation drugs, including the p300/CREB binding protein-associated factor activator pentadecylidenemalonate 1b (SPV106). Any response to GTN was abolished by anacardic acid, a potent histone acetylases inhibitor. This study establishes the following points: (1) GTN treatment increases histone acetylases activity; (2) GTN-activated p300/CREB binding protein-associated factor increases protein N(ε)-lysine acetylation; (3) N(ε)-lysine acetylation of contractile proteins influences GTN-dependent vascular response. Hence, combination of epigenetic drugs and nitroglycerin may be envisaged as a novel treatment strategy for coronary artery disease symptoms and other cardiovascular accidents of ischemic origin.
  Arteriosclerosis Thrombosis and Vascular Biology 08/2012; 32(10):2435-43. · 6.37 Impact Factor
• Article: Patient profile modulates cardiac c-kit(+) progenitor cell availability and amplification potential.

  Elisa Gambini, Maurizio Pesce, Luca Persico, Beatrice Bassetti, Antonio Gambini, Francesco Alamanni, Marco Agrifoglio, Maurizio C Capogrossi, Giulio Pompilio
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  ABSTRACT: Human c-kit(+) cardiac progenitor cells (CPCs) are multipotent and may be used for cardiac repair. The effect of cardiovascular risk factors and medications on CPCs isolation efficiency, c-kit stem cell marker expression, and ex vivo proliferative potential is unknown and was examined in the present work. Cells from human right atrial appendages (n = 50) were expanded in culture; after ∼16 days (T0), it was established the percentage of CPCs and c-kit protein mean fluorescence intensity (MFI) by fluorescence activated cell sorting (FACS). Thereafter, CPCs were isolated by high throughput sorting; after culturing for 4 passages CPCs-derived cells were re-analyzed to assess c-kit(+) cell percentage and enrichment vs T0. The association between 19 demographic and clinical variables to CPCs number and MFI at T0, and CPCs enrichment at P4, was determined by multiple linear regression analysis with stepwise selection procedure. The results revealed that (1) at T0, the number of isolated CPCs directly correlated to β-blocker treatment; (2) at T0, c-kit protein expression directly correlated to pulmonary hypertension (PH); (3) at P4, CPC's enrichment inversely correlated to smoke, atrial fibrillation (AF), a history of myocardial infarction, whereas it directly correlated to PH and statins. Patient clinical profile and medications differently modulate CPCs isolation and amplification potential ex vivo. These results may provide new insights for the understanding of cardiac homeostasis and suggest both limitations and possible enhancing strategies for the therapeutic use of cardiac-resident progenitor cells.
  Translational research : the journal of laboratory and clinical medicine. 06/2012; 160(5):363-73.
• Source

  Available from: Giovanni Tinelli

  Article: Differences in microparticle release in patients with acute coronary syndrome and stable angina.

  Luigi Marzio Biasucci, Italo Porto, Luca Di Vito, Giovanni Luigi De Maria, Antonio Maria Leone, Giovanni Tinelli, Alessandra Tritarelli, Giuliana Di Rocco, Francesco Snider, Maurizio C Capogrossi, Filippo Crea
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  ABSTRACT: Background: Microparticles (MP) are vesicles released from activated or apoptotic cells. Endothelial MP (EMP) are derived from injured endothelium, platelet MP (PMP) from activated platelets, and Annexin V positive MP (AMP) from apoptotic endothelial cells. The aim was to assess the release of MP and its association with inflammation and atherosclerotic burden. Methods and Results: AMP, EMP and PMP were measured on admission (Day 0) in 33 patients with stable angina (SA) and 43 patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCI). In SA, peripheral artery disease (PAD) was assessed by ultrasound examination. In 30 of the 76 patients (20 ACS and 10 SA), MP, high-sensitivity-C-reactive protein (hs-CRP), and troponin T (TnT) levels were also assessed 24h (Day 1) and 48h (Day 2) after PCI. AMP, EMP, and PMP were higher in ACS than in SA (all P<0.01). In the SA group, AMP, PMP, and EMP were similar in patients with or without PAD. In the ACS group, AMP increased until Day 2 (P=0.001), while EMP and PMP peaked on Day 1 (P<0.01) then decreased to baseline values. Day 2 AMP correlated with Day 2 TnT levels (r=0.43, P=0.01) while Day 1 EMP and PMP correlated with Day 1 hs-CRP (r=0.37, P=0.04 and r=0.33, P=0.05; respectively). Conclusions: Higher MP levels were observed in ACS than in SA. Atherosclerotic burden did not affect MP levels in stable patients.  (Circ J 2012; 76: 2174-2182).
  Circulation Journal 06/2012; 76(9):2174-82. · 3.77 Impact Factor
• Article: MicroRNAs and myocardial infarction.

  Yuri D'Alessandra, Giulio Pompilio, Maurizio C Capogrossi
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  ABSTRACT: We will review the role of microRNAs (miRNAs), small noncoding RNAs with regulatory function, in myocardial infarction (MI). Specifically, we will examine the effect of MI on miRNAs' expression in the heart, the effect of MI on circulating miRNAs, which miRNAs' overexpression or downmodulation appears to have a therapeutic role in MI and which cardiac miRNAs are modulated by drugs/experimental molecules/cell transplantation strategies which have an established or potential therapeutic role in MI. A rapidly increasing number of studies are showing that cardiac and circulating miRNAs are markedly altered in MI. These novel findings shed new light on the mechanisms that lead to MI complications, post-MI ventricular remodeling and cardiac repair. Further, recent studies show that circulating miRNAs may represent novel and sensitive biomarkers of MI and, possibly, also an intercellular signaling mechanism. Overexpression and downregulation of specific miRNAs are being evaluated as a novel approach to the treatment of MI. Finally, it appears that some established and potential MI therapies (approved drugs/experimental molecules/cell therapy interventions) may act, at least in part, via modulation of specific miRNAs. Although miRNAs' role in MI is still largely uncharacterized, recent studies suggest that miRNAs may represent novel therapeutic targets and MI biomarkers.
  Current opinion in cardiology 05/2012; 27(3):228-35. · 2.66 Impact Factor
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  Available from: Domenico A Coviello

  Article: Human chorionic villus mesenchymal stromal cells reveal strong endothelial conversion properties.

  Viviana Meraviglia, Matteo Vecellio, Annalisa Grasselli, Marco Baccarin, Antonella Farsetti, Maurizio C Capogrossi, Giulio Pompilio, Domenico A Coviello, Carlo Gaetano, Marina Di Segni, Alessandra Rossini
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  ABSTRACT: Chorion, amnion and villi are reservoirs of mesenchymal stromal cells (StC) and the hypothesis that StC from fetal tissues retain higher plasticity compared to adult StC has been suggested. Aimed at investigating this aspect, a series of in vitro experiments were performed with StC isolated from first trimester human chorionic villi (CVStC). CVStC were cultured in: (i) standard mesenchymal medium (MM) and (ii) AmniomaxII® (AM), specifically designed to grow amnion-derived cells in prenatal diagnostic procedures. Cells were then exposed to distinct differentiation treatments and distinguished according to morphology, immunophenotype and molecular markers. Human StC obtained from adult bone marrow (BMStC) were used as control. CVStC cultured either in MM or AM presented stromal morphology and immunophenotype, were negative for pluripotency factors (Nanog, Oct-4 and Sox-2), lacked detectable telomerase activity and retained high genomic stability. In AM, however, CVStC exhibited a faster proliferation rate compared to BMStC or CVStC kept in MM. During differentiation, CVStC were less efficient than BMStC in acquiring adipocytes and osteocytes features; the cardiomyogenic conversion occurred at low efficiency in both cell types. Remarkably, in the presence of pro-angiogenic factors, CVStC reprogrammed toward an endothelial-like phenotype at significantly higher efficiency than BMStC. This effect was particularly evident in CVStC expanded in AM. Mechanistically, the reduced CVStC expression of anti-angiogenic microRNA could support this process. The present study demonstrates that, despite of fetal origin, CVStC exhibit restricted plasticity, distinct from that of BMStC and predominantly directed toward the endothelial lineage.
  Differentiation 03/2012; 83(5):260-70. · 2.81 Impact Factor
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  Available from: Gabriele Toietta

  Article: ANALYSIS OF BIODISTRIBUTION AND ENGRAFTMENT INTO THE LIVER OF GENETICALLY-MODIFIED MESENCHYMAL STROMAL CELLS DERIVED FROM ADIPOSE TISSUE.

  Giuliana Di Rocco, Antonietta Gentile, Annalisa Antonini, Silvia Truffa, Giulia Piaggio, Maurizio C Capogrossi, Gabriele Toietta
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  ABSTRACT: Presently, orthotopic liver transplant is the major therapeutic option for patients affected by primary liver diseases. This procedure is characterized by major invasive surgery, scarcity of donor organs, high costs, and lifelong immunosuppressive treatment. Transplant of hepatic precursor cells represents an attractive alternative. These cells could be used either for allogeneic transplantation or for autologous transplant after ex vivo genetic modification. We used stromal cells isolated from adipose tissue (AT-SCs) as platforms for autologous cell-mediated gene therapy. AT-SCs were transduced with lentiviral vectors expressing firefly luciferase, allowing for transplanted cell tracking by bioluminescent imaging (BLI). As a complementary approach, we followed circulating human α1-antitrypsin (hAAT) levels after infusion of AT-SCs overexpressing hAAT. Cells were transplanted into syngeneic mice after CCl₄-induced hepatic injury. Luciferase bioluminescence signals and serum hAAT levels were measured at different time points after transplantation and demonstrate persistence of transplanted cells for up to 2 months after administration. These data, along with immunohistochemical analysis, suggest engraftment and repopulation of injured livers by transplanted AT-SCs. Moreover, by transcriptional targeting using cellular tissue-specific regulatory sequences we confirmed that AT-SCs differentiate towards a hepatogenic-like phenotype in vitro and in vivo. Additionally, in transplanted cells re-isolated from recipient animals ' livers we detected activation of the alpha-fetoprotein (AFP) promoter. This promoter is normally transcriptionally silenced in adult tissues but can be re-activated during liver regeneration, suggesting commitment towards hepatogenic-like differentiation of engrafted cells in vivo. Our data support AT-SC cell-mediated gene therapy as an innovative therapeutic option for disorders of liver metabolism.
  Cell Transplantation 03/2012; · 5.13 Impact Factor
• Article: The SDF-1/CXCR4 axis in stem cell preconditioning.

  Chiara Cencioni, Maurizio C Capogrossi, Monica Napolitano
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  ABSTRACT: We review the pivotal role of the stromal derived factor (SDF)-1 chemokine in tissue ischaemia and how it orchestrates the rapid revascularization of injured, ischaemic, and regenerating tissues via the CXC chemokine receptors CXCR4 and CXCR7. Furthermore, we discuss the effects of preconditioning (PC), which is a well-known protective phenomenon for tissue ischaemia. The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process.
  Cardiovascular research 03/2012; 94(3):400-7. · 5.80 Impact Factor
• Article: C/EBPγ regulates wound repair and EGF receptor signaling.

  Roberta Melchionna, Gabriella Bellavia, Marta Romani, Stefania Straino, Antonia Germani, Anna Di Carlo, Maurizio C Capogrossi, Monica Napolitano
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  ABSTRACT: We aimed at identifying novel regulators of skin wound healing (WH), in an epidermal scratch WH assay, by a small interfering RNA (siRNA) silencing approach. Several transcription factors have been previously reported to affect wound repair. We here show that gene silencing of the transcription factor CAAT enhancer-binding protein γ (C/EBPγ), STAT3, REL, RELA, RELB, SP1, and NFkB impaired WH in vitro, in keratinocytes, whereas E2F and CREBBP silencing accelerated the WH process. We further characterized C/EBPγ, as its silencing yielded the maximal impairment (52.2 ± 12.5%) of scratch wounding (SW). We found that C/EBPγ silencing inhibited both EGF- and serum-induced keratinocyte migration, whereas C/EBPγ overexpression enhanced cell migration to EGF and to serum via the EGFR. Further, C/EBPγ silencing impaired scratch-induced Y1068 and Y1173 EGFR phosphorylation, as well as Y118 paxillin phosphorylation, key molecules regulating cell migration and epidermal WH. Moreover, C/EBPγ levels were induced in keratinocytes, following both SW and EGF stimulation. C/EBPγ siRNA silencing in vivo impaired WH at 3, 5, 7, and 14 days following excisional wounding in mice inhibited both re-epithelialization and granulation tissue formation, and induced a decrease of arteriole number. In conclusion, we here report that C/EBPγ positively regulates wound repair both in vitro and in vivo, at least in part, by affecting EGFR signaling.
  Journal of Investigative Dermatology 03/2012; 132(7):1908-17. · 6.31 Impact Factor
• Article: MicroRNA dysregulation in diabetic ischemic heart failure patients.

  Simona Greco, Pasquale Fasanaro, Serenella Castelvecchio, Yuri D'Alessandra, Diego Arcelli, Marisa Di Donato, Alexis Malavazos, Maurizio C Capogrossi, Lorenzo Menicanti, Fabio Martelli
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  ABSTRACT: Increased morbidity and mortality associated with ischemic heart failure (HF) in type 2 diabetic patients requires a deeper understanding of the underpinning pathogenetic mechanisms. Given the implication of microRNAs (miRNAs) in HF, we investigated their regulation and potential role. miRNA expression profiles were measured in left ventricle biopsies from 10 diabetic HF (D-HF) and 19 nondiabetic HF (ND-HF) patients affected by non-end stage dilated ischemic cardiomyopathy. The HF groups were compared with each other and with 16 matched nondiabetic, non-HF control subjects. A total of 17 miRNAs were modulated in D-HF and/or ND-HF patients when compared with control subjects. miR-216a, strongly increased in both D-HF and ND-HF patients, negatively correlated with left ventricular ejection fraction. Six miRNAs were differently expressed when comparing D-HF and ND-HF patients: miR-34b, miR-34c, miR-199b, miR-210, miR-650, and miR-223. Bioinformatic analysis of their modulated targets showed the enrichment of cardiac dysfunctions and HF categories. Moreover, the hypoxia-inducible factor pathway was activated in the noninfarcted, vital myocardium of D-HF compared with ND-HF patients, indicating a dysregulation of the hypoxia response mechanisms. Accordingly, miR-199a, miR-199b, and miR-210 were modulated by hypoxia and high glucose in cardiomyocytes and endothelial cells cultured in vitro. In conclusion, these findings show a dysregulation of miRNAs in HF, shedding light on the specific disease mechanisms differentiating diabetic patients.
  Diabetes 03/2012; 61(6):1633-41. · 8.29 Impact Factor
• Article: Deep-sequencing of endothelial cells exposed to hypoxia reveals the complexity of known and novel microRNAs.

  Christine Voellenkle, Jeroen van Rooij, Alessandro Guffanti, Elena Brini, Pasquale Fasanaro, Eleonora Isaia, Larry Croft, Matei David, Maurizio C Capogrossi, Anna Moles, Armando Felsani, Fabio Martelli
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  ABSTRACT: In order to understand the role of microRNAs (miRNAs) in vascular physiopathology, we took advantage of deep-sequencing techniques to accurately and comprehensively profile the entire miRNA population expressed by endothelial cells exposed to hypoxia. SOLiD sequencing of small RNAs derived from human umbilical vein endothelial cells (HUVECs) exposed to 1% O₂ or normoxia for 24 h yielded more than 22 million reads per library. A customized bioinformatic pipeline identified more than 400 annotated microRNA/microRNA* species with a broad abundance range: miR-21 and miR-126 totaled almost 40% of all miRNAs. A complex repertoire of isomiRs was found, displaying also 5' variations, potentially affecting target recognition. High-stringency bioinformatic analysis identified microRNA candidates, whose predicted pre-miRNAs folded into a stable hairpin. Validation of a subset by qPCR identified 18 high-confidence novel miRNAs as detectable in independent HUVEC cultures and associated to the RISC complex. The expression of two novel miRNAs was significantly down-modulated by hypoxia, while miR-210 was significantly induced. Gene ontology analysis of their predicted targets revealed a significant association to hypoxia-inducible factor signaling, cardiovascular diseases, and cancer. Overexpression of the novel miRNAs in hypoxic endothelial cells affected cell growth and confirmed the biological relevance of their down-modulation. In conclusion, deep-sequencing accurately profiled known, variant, and novel microRNAs expressed by endothelial cells in normoxia and hypoxia.
  RNA 03/2012; 18(3):472-84. · 5.09 Impact Factor
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  Available from: Gabriele Toietta

  Article: Molecular imaging of nuclear factor-Y transcriptional activity maps proliferation sites in live animals.

  Frauke Goeman, Isabella Manni, Simona Artuso, Balaji Ramachandran, Gabriele Toietta, Gianluca Bossi, Gianpaolo Rando, Chiara Cencioni, Sabrina Germoni, Stefania Straino, Maurizio C Capogrossi, Silvia Bacchetti, Adriana Maggi, Ada Sacchi, Paolo Ciana, Giulia Piaggio
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  ABSTRACT: In vivo imaging involving the use of genetically engineered animals is an innovative powerful tool for the noninvasive assessment of the molecular and cellular events that are often targets of therapy. On the basis of the knowledge that the activity of the nuclear factor-Y (NF-Y) transcription factor is restricted in vitro to proliferating cells, we have generated a transgenic reporter mouse, called MITO-Luc (for mitosis-luciferase), in which an NF-Y-dependent promoter controls luciferase expression. In these mice, bioluminescence imaging of NF-Y activity visualizes areas of physiological cell proliferation and regeneration during response to injury. Using this tool, we highlight for the first time a role of NF-Y activity on hepatocyte proliferation during liver regeneration. MITO-Luc reporter mice should facilitate investigations into the involvement of genes in cell proliferation and provide a useful model for studying aberrant proliferation in disease pathogenesis. They should be also useful in the development of new anti/proproliferative drugs and assessment of their efficacy and side effects on nontarget tissues.
  Molecular biology of the cell 02/2012; 23(8):1467-74. · 5.98 Impact Factor