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Voellenkle C.,Laboratorio Of Cardiologia Molecolare | Van Rooij J.,Laboratorio Of Cardiologia Molecolare | Cappuzzello C.,Centro Cardiologico Monzino IRCCS | Greco S.,Laboratorio Of Cardiologia Molecolare | And 9 more authors.
Physiological Genomics | Year: 2010

MicroRNAs (miRNAs) are noncoding RNAs that act as negative regulators of gene expression. Interestingly, specific alterations of miRNA expression have been found in failing hearts of different etiologies. The aim of this study was to identify the miRNA expression pattern of peripheral blood mononuclear cells (PBMCs) derived from chronic heart failure (CHF) patients affected by ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. The expression profile of 257 miRNAs was assessed in 7 NIDCM patients, 8 ICM patients, and 9 control subjects by quantitative real-time PCR. Significantly modulated miRNAs were validated by using an independent set of 34 CHF patients (NIDCM = 19, ICM = 15) and 19 control subjects. Three miRNAs (miR-107, -139, and -142-5p) were downmodulated in both NIDCM and ICM patients versus control subjects. Other miRNAs were deregulated in only one of the CHF classes analyzed compared with control subjects: miR-142-3p and -29b were increased in NIDCM patients, while miR-125b and -497 were decreased in ICM patients. Bioinformatic analysis of miRNA predicted targets and of gene expression modifications associated with CHF in PBMCs indicated a significant impact of the miRNA signature on the transcriptome. Furthermore, miRNAs of both the NIDCM and the ICM signature shared predicted targets among CHF-modulated genes, suggesting potential additive or synergistic effects. The present study identified miRNAs specifically modulated in the PBMCs of NIDCM and ICM patients. Intriguingly, most of these miRNAs were previously reported as deregulated in human and/or mouse failing hearts. The identified miRNAs might have a potential diagnostic and/or prognostic use in CHF. Copyright © 2010 the American Physiological Society.


Spallotta F.,Instituto Of Ricerca E Cura A Carattere Scientifico | Spallotta F.,Goethe University Frankfurt | Cencioni C.,Instituto Of Ricerca E Cura A Carattere Scientifico | Cencioni C.,Goethe University Frankfurt | And 14 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Nitric oxide (NO) regulates class I and IIa histone deacetylase (HDAC) function. NO production is regulated by class III HDACs (sirtuins). Results: NO functions as a bridging molecule between class I and sirtuins (SIRTs). Conclusion: The SIRT-NO-class I HDAC axis provides key signals during wound repair. Significance: Modulation of HDAC activity may play an important role in tissue regeneration. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Spallotta F.,Centro Cardiologico Monzino | Spallotta F.,Goethe University Frankfurt | Cencioni C.,Centro Cardiologico Monzino | Cencioni C.,Goethe University Frankfurt | And 6 more authors.
Communicative and Integrative Biology | Year: 2013

In physiopathological conditions, such as diabetes, wound healing is significantly compromised and chronic complications, including ulcers, may occur. In a mouse model of skin repair, we recently reported that wound treatment with Sirtuin activators and class I HDAC inhibitors induced keratinocyte proliferation and enhanced healing via a nitric oxide (NO) dependent mechanism. We observed an increase in total protein acetylation in the wound area, as determined by acetylation of a-tubulin and histone H3 Lysine 9. We reasoned that this process activated cell function as well as regulated gene expression to foster tissue repair. We report here that the direct activation of P300/CBP-associated factor (PCAF) by the histone acetylase activator pentadecylidenemalonate 1b (SPV-106) induced Lysine acetylation in the wound area. This intervention was sufficient to enhance repair process by a NO-independent mechanism. Hence, an impairment of PCAF and/or other GCN5 family acetylases may delay skin repair in physiopathological conditions. © 2013 Landes Bioscience.


Fasanaro P.,Laboratorio Of Cardiologia Molecolare | Greco S.,Laboratorio Of Cardiologia Molecolare | Ivan M.,Indiana University | Capogrossi M.C.,Instituto Dermopatico dellImmacolata IRCCS | Martelli F.,Instituto Dermopatico dellImmacolata IRCCS
Pharmacology and Therapeutics | Year: 2010

microRNAs (miRNAs) are 21-23-nucleotide non-protein-coding RNA molecules that act as negative regulators of gene expression, modulating the stability and/or the translational efficiency of target messenger RNAs. This review describes miRNA regulation and function in tissue response to acute ischemia. We focused our attention on a subset of miRNAs that have been found de-regulated in different studies, suggesting that they may represent "master ischemic" miRNAs, playing a pathogenetic role in different components of tissue response to ischemia. First, we analyzed the role of miRNAs in cell response to hypoxia, a crucial component of ischemia, and in angiogenesis. Then, we describe miRNAs role in acute myocardial infarction as much as in hindlimb, cerebral, hepatic and retinal ischemia. The role played by specific miRNAs in the regulation of apoptosis, fibrosis, regeneration and myocardial arrhythmias is illustrated. The identification of specific miRNAs as key regulators of the response to ischemia has opened new clinical avenues. miRNAs may constitute excellent non-invasive disease biomarkers. Furthermore, innovative strategies targeting miRNAs, aimed to reduce the levels of pathogenic or aberrantly expressed miRNAs or to elevate the levels of miRNAs with beneficial functions, have been developed and could be applied in the treatment of ischemic diseases. © 2009 Elsevier Inc. All rights reserved.


Voellenkle C.,Laboratorio Of Cardiologia Molecolare | Van Rooij J.,Laboratorio Of Cardiologia Molecolare | Guffanti A.,Genomnia Srl | Brini E.,Genomnia Srl | And 8 more authors.
RNA | Year: 2012

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% O 2 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. Highstringency 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 hypoxiainducible 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.


Magenta A.,Instituto Dermopatico dell0Immacolata | Cencioni C.,Centro Cardiologico Monzino IRCCS | Fasanaro P.,Laboratorio Of Cardiologia Molecolare | Zaccagnini G.,Laboratorio Of Cardiologia Molecolare | And 5 more authors.
Cell Death and Differentiation | Year: 2011

We examined the effect of reactive oxygen species (ROS) on MicroRNAs (miRNAs) expression in endothelial cells in vitro, and in mouse skeletal muscle following acute hindlimb ischemia. Human umbilical vein endothelial cells (HUVEC) were exposed to 200 M hydrogen peroxide (H 2 O 2) for 8 tO 24 h; miRNAs profiling showed that miR-200c and the co-transcribed miR-141 increased more than eightfold. The other miR-200 gene family members were also induced, albeit to a lower level. Furthermore, miR-200c upregulation was not endothelium restricted, and occurred also on exposure to an oxidative stress-inducing drug: 1,3-bis(2 chloroethyl)-1nitrosourea (BCNU). miR-200c overexpression induced HUVEC growth arrest, apoptosis and senescence; these phenomena were also induced by H 2 O 2 and were partially rescued by miR-200c inhibition. Moreover, miR-200c target ZEB1 messenger RNA and protein were downmodulated by H 2 O 2 and by miR-200c overexpression. ZEB1 knockdown recapitulated miR-200c-induced responses, and expression of a ZEB1 allele non-targeted by miR-200c, prevented miR-200c phenotype. The mechanism of H 2 O 2-mediated miR-200c upregulation involves p53 and retinoblastoma proteins. Acute hindlimb ischemia enhanced miR-200c in wild-type mice skeletal muscle, whereas in p66 ShcA/mice, which display lower levels of oxidative stress after ischemia, upregulation of miR-200c was markedly inhibited. In conclusion, ROS induce miR-200c and other miR-200 family members; the ensuing downmodulation of ZEB1 has a key role in ROS-induced apoptosis and senescence. © 2011 Macmillan Publishers Limited All rights reserved.


Mariotti S.,Laboratorio Of Cardiologia Molecolare | Capparuccia C.,U.O. di Cardiologia UTIC | Ripa C.,U.O. di Cardiologia UTIC | Olivieri F.,Laboratorio Of Cardiologia Molecolare | And 4 more authors.
Giornale Italiano di Cardiologia | Year: 2010

The aim of this review is to emphasize the role of molecular biology in the diagnosis and therapy of major cardiomyopathies and cardiovascular risk factors. Therefore, we have underlined the genes responsible for or associated with these diseases while highlighting a role in the response to therapy (pharmacogenomics). Cardiovascular diseases and its related risk factors were divided into monogenic and polygenic forms. Monogenic forms are much rarer in clinical practice. However, polygenic forms along with most risk factors are of important clinical interest due to their high frequency in the general population. The added value of genetic testing is to provide an individual risk profile assessed in each patient and not only derived from epidemiological data. The prognosis of patients with the same risk profile, assessed using current clinical and medical history data, is often very different. An accurate prediction of the clinical course of cardiovascular disease in each patient will be the best therapeutic approach (tailored medicine) and will also result in a significant cost reduction for national healthcare systems (effective therapy). © 2010 AIM Publishing Srl.


PubMed | Laboratorio Of Cardiologia Molecolare
Type: Journal Article | Journal: Giornale italiano di cardiologia (2006) | Year: 2011

The aim of this review is to emphasize the role of molecular biology in the diagnosis and therapy of major cardiomyopathies and cardiovascular risk factors. Therefore, we have underlined the genes responsible for or associated with these diseases while highlighting a role in the response to therapy (pharmacogenomics). Cardiovascular diseases and its related risk factors were divided into monogenic and polygenic forms. Monogenic forms are much rarer in clinical practice. However, polygenic forms along with most risk factors are of important clinical interest due to their high frequency in the general population. The added value of genetic testing is to provide an individual risk profile assessed in each patient and not only derived from epidemiological data. The prognosis of patients with the same risk profile, assessed using current clinical and medical history data, is often very different. An accurate prediction of the clinical course of cardiovascular disease in each patient will be the best therapeutic approach (tailored medicine) and will also result in a significant cost reduction for national healthcare systems (effective therapy).


PubMed | Laboratorio Of Cardiologia Molecolare
Type: Journal Article | Journal: Pharmacology & therapeutics | Year: 2010

microRNAs (miRNAs) are 21-23-nucleotide non-protein-coding RNA molecules that act as negative regulators of gene expression, modulating the stability and/or the translational efficiency of target messenger RNAs. This review describes miRNA regulation and function in tissue response to acute ischemia. We focused our attention on a subset of miRNAs that have been found de-regulated in different studies, suggesting that they may represent master ischemic miRNAs, playing a pathogenetic role in different components of tissue response to ischemia. First, we analyzed the role of miRNAs in cell response to hypoxia, a crucial component of ischemia, and in angiogenesis. Then, we describe miRNAs role in acute myocardial infarction as much as in hindlimb, cerebral, hepatic and retinal ischemia. The role played by specific miRNAs in the regulation of apoptosis, fibrosis, regeneration and myocardial arrhythmias is illustrated. The identification of specific miRNAs as key regulators of the response to ischemia has opened new clinical avenues. miRNAs may constitute excellent non-invasive disease biomarkers. Furthermore, innovative strategies targeting miRNAs, aimed to reduce the levels of pathogenic or aberrantly expressed miRNAs or to elevate the levels of miRNAs with beneficial functions, have been developed and could be applied in the treatment of ischemic diseases.

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