Publications by authors named "Fabio Martelli"

102 Publications

Leveraging non-coding RNAs to fight cardiovascular disease: the EU-CardioRNA network.

Eur Heart J 2021 Jun 10. Epub 2021 Jun 10.

Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

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http://dx.doi.org/10.1093/eurheartj/ehab326DOI Listing
June 2021

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Leuven, Belgium.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
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http://dx.doi.org/10.1126/sciadv.abf0466DOI Listing
May 2021

Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia.

Cell Death Dis 2021 May 1;12(5):435. Epub 2021 May 1.

Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097, San Donato Milanese, Milan, Italy.

Hypoxia-induced miR-210 is a crucial component of the tissue response to ischemia, stimulating angiogenesis and improving tissue regeneration. Previous analysis of miR-210 impact on the transcriptome in a mouse model of hindlimb ischemia showed that miR-210 regulated not only vascular regeneration functions, but also inflammation. To investigate this event, doxycycline-inducible miR-210 transgenic mice (Tg-210) and anti-miR-210 LNA-oligonucleotides were used. It was found that global miR-210 expression decreased inflammatory cells density and macrophages accumulation in the ischemic tissue. To dissect the underpinning cell mechanisms, Tg-210 mice were used in bone marrow (BM) transplantation experiments and chimeric mice underwent hindlimb ischemia. MiR-210 overexpression in the ischemic tissue was sufficient to increase capillary density and tissue repair, and to reduce inflammation in the presence of Wt-BM infiltrating cells. Conversely, when Tg-210-BM cells migrated in a Wt ischemic tissue, dysfunctional angiogenesis, inflammation, and impaired tissue repair, accompanied by fibrosis were observed. The fibrotic regions were positive for α-SMA, Vimentin, and Collagen V fibrotic markers and for phospho-Smad3, highlighting the activation of TGF-β1 pathway. Identification of Tg-210 cells by in situ hybridization showed that BM-derived cells contributed directly to fibrotic areas, where macrophages co-expressing fibrotic markers were observed. Cell cultures of Tg-210 BM-derived macrophages exhibited a pro-fibrotic phenotype and were enriched with myofibroblast-like cells, which expressed canonical fibrosis markers. Interestingly, inhibitors of TGF-β type-1-receptor completely abrogated this pro-fibrotic phenotype. In conclusion, a context-dependent regulation by miR-210 of the inflammatory response was identified. miR-210 expression in infiltrating macrophages is associated to improved angiogenesis and tissue repair when the ischemic recipient tissue also expresses high levels of miR-210. Conversely, when infiltrating an ischemic tissue with mismatched miR-210 levels, macrophages expressing high miR-210 levels display a pro-fibrotic phenotype, leading to impaired tissue repair, fibrosis, and dysfunctional angiogenesis.
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http://dx.doi.org/10.1038/s41419-021-03713-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088433PMC
May 2021

Cardiovascular rna markers and artificial intelligence may improve covid-19 outcome: position paper from the eu-cardiorna cost action ca17129.

Cardiovasc Res 2021 Apr 11. Epub 2021 Apr 11.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg.

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of February 8th, 2020 and causing more than 2.3 million deaths according the World Health Organization. Not only affecting the lungs and provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts and the added value of artificial intelligence to achieve reliable advances.
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http://dx.doi.org/10.1093/cvr/cvab094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083253PMC
April 2021

Covid-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Department of Biomedical Sciences for Health, Chair of Clinical Pathology, University of Milan, I-20133 Milan, Italy.

Coronavirus Disease 2019 (COVID-19)-associated coagulopathy is characterized by a prothrombotic state not yet comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS), comparing patients who survived to those who did not. In this prospective cohort study on 20 COVID-19 ARDS patients, the following biomarkers were measured: thrombin generation (prothrombin fragment 1 + 2 (PF 1 + 2)), fibrinolysis activation (tissue plasminogen activator (tPA)) and inhibition (plasminogen activator inhibitor 2 (PAI-2)), fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex (PAP) and D-dimers). Measurements were done upon intensive care unit (ICU) admission and after 10-14 days. There was increased thrombin generation; modest or null release of t-PA; and increased levels of PAI-2, fibrinopeptide A, PAP and D-dimers. At baseline, nonsurvivors had a significantly ( = 0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range (IQR) 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly ( = 0.025) reduced in survivors (PF 1 + 2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in nonsurvivors. Fibrinolysis inhibition at follow-up remained stable in survivors and increased in nonsurvivors, leading to a significant ( = 0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1088 pg/mL, IQR 177-1565). Severe patterns of COVID-19 ARDS are characterized by a thrombin burst and the consequent coagulation activation. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. This pattern ameliorates in survivors, whereas it worsens in nonsurvivors.
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http://dx.doi.org/10.3390/jcm9113487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692774PMC
October 2020

Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases.

Int J Mol Sci 2020 Oct 27;21(21). Epub 2020 Oct 27.

Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 4, 27100 Pavia, Italy.

The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non-senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases.
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http://dx.doi.org/10.3390/ijms21217984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663758PMC
October 2020

The epigenetic implication in coronavirus infection and therapy.

Clin Epigenetics 2020 10 21;12(1):156. Epub 2020 Oct 21.

Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 4, 27100, Pavia, Italy.

Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.
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http://dx.doi.org/10.1186/s13148-020-00946-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576975PMC
October 2020

Approaching Sex Differences in Cardiovascular Non-Coding RNA Research.

Int J Mol Sci 2020 Jul 10;21(14). Epub 2020 Jul 10.

Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, and INCLIVA Biomedical Research Institute, Menéndez Pelayo 4 Accesorio, 46010 Valencia, Spain.

Cardiovascular disease (CVD) is the biggest cause of sickness and mortality worldwide in both males and females. Clinical statistics demonstrate clear sex differences in risk, prevalence, mortality rates, and response to treatment for different entities of CVD. The reason for this remains poorly understood. Non-coding RNAs (ncRNAs) are emerging as key mediators and biomarkers of CVD. Similarly, current knowledge on differential regulation, expression, and pathology-associated function of ncRNAs between sexes is minimal. Here, we provide a state-of-the-art overview of what is known on sex differences in ncRNA research in CVD as well as discussing the contributing biological factors to this sex dimorphism including genetic and epigenetic factors and sex hormone regulation of transcription. We then focus on the experimental models of CVD and their use in translational ncRNA research in the cardiovascular field. In particular, we want to highlight the importance of considering sex of the cellular and pre-clinical models in clinical studies in ncRNA research and to carefully consider the appropriate experimental models most applicable to human patient populations. Moreover, we aim to identify sex-specific targets for treatment and diagnosis for the biggest socioeconomic health problem globally.
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http://dx.doi.org/10.3390/ijms21144890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402336PMC
July 2020

RNAs in Brain and Heart Diseases.

Int J Mol Sci 2020 May 25;21(10). Epub 2020 May 25.

Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

In the era of single-cell analysis, one always has to keep in mind the systemic nature of various diseases and how these diseases could be optimally studied. Comorbidities of the heart in neurological diseases as well as of the brain in cardiovascular diseases are prevalent, but how interactions in the brain-heart axis affect disease development and progression has been poorly addressed. Several brain and heart diseases share common risk factors. A better understanding of the brain-heart interactions will provide better insights for future treatment and personalization of healthcare, for heart failure patients' benefit notably. We review here emerging evidence that studying noncoding RNAs in the brain-heart axis could be pivotal in understanding these interactions. We also introduce the Special Issue of the International Journal of Molecular Sciences RNAs in Brain and Heart Diseases-EU-CardioRNA COST Action.
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http://dx.doi.org/10.3390/ijms21103717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279324PMC
May 2020

A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease.

Noncoding RNA 2020 05 18;6(2). Epub 2020 May 18.

Cardiovascular Research Unit, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action.
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http://dx.doi.org/10.3390/ncrna6020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345156PMC
May 2020

Dysregulation of microRNA expression in diabetic skin.

J Dermatol Sci 2020 06 4;98(3):186-194. Epub 2020 May 4.

Lab. Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via dei Monti di Creta, Rome, Italy. Electronic address:

Background: Clinical skin manifestations are common in diabetes; however, molecular mechanisms underlying such defects are largely unknown. Several findings indicate a role for microRNAs (miRNAs) in skin homeostasis.

Objective: To investigate whether miRNA expression is altered in diabetic skin.

Methods: Type 1 and 2 mouse models of diabetes were used. MiRNA profiling was performed on RNA extracted from the skin of type 1 diabetic mice and non-diabetic controls. Expression levels of pri-miRNAs and of miRNA-biogenesis genes were also analyzed. Biogenesis gene expression analysis was performed in human dermal fibroblasts cultured in hyperglycemic, hypoxic or oxidative stress conditions.

Results: Several miRNAs were differentially expressed in diabetic skin with a general down-modulation as compared to controls. Bioinformatics analysis of signature-miRNA target genes showed the enrichment in pathways involved in skin homeostasis, such as TGF-β and Wnt. MiRNA alteration in diabetic skin associated with reduced expression levels of DROSHA, DGCR8, XPO5, DICER1, AGO2, both as mRNA and protein. Reduced biogenesis gene expression did not correlate with accumulation of pri-miRNAs, which displayed differences in expression levels similar to those found for their mature miRNAs. Experiments with cultured fibroblasts showed that hypoxia and oxidative stress induced the down-regulation of miRNA-biogenesis genes in this skin cell type.

Conclusion: A general down-regulation of differentially expressed miRNAs was found in diabetic skin. This alteration is part of and is dependent from a wider transcriptional defect also affecting the expression of pri-miRNAs and of genes responsible for miRNA biogenesis. Such an alteration is likely contributing to diabetic skin manifestations.
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http://dx.doi.org/10.1016/j.jdermsci.2020.04.009DOI Listing
June 2020

Call to action for the cardiovascular side of COVID-19.

Eur Heart J 2020 05;41(19):1796-1797

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg.

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http://dx.doi.org/10.1093/eurheartj/ehaa301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529147PMC
May 2020

Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis.

Cells 2020 03 2;9(3). Epub 2020 Mar 2.

National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.

Fibrosis is a significant global health problem associated with many inflammatory and degenerative diseases affecting multiple organs, individually or simultaneously. Fibrosis develops when extracellular matrix (ECM) remodeling becomes excessive or uncontrolled and is associated with nearly all forms of heart disease. Cardiac fibroblasts and myofibroblasts are the main effectors of ECM deposition and scar formation. The heart is a complex multicellular organ, where the various resident cell types communicate between themselves and with cells of the blood and immune systems. Exosomes, which are small extracellular vesicles, (EVs), contribute to cell-to-cell communication and their pathophysiological relevance and therapeutic potential is emerging. Here, we will critically review the role of endogenous exosomes as possible fibrosis mediators and discuss the possibility of using stem cell-derived and/or engineered exosomes as anti-fibrotic agents.
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http://dx.doi.org/10.3390/cells9030592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140485PMC
March 2020

Regulatory RNAs in Heart Failure.

Circulation 2020 01 27;141(4):313-328. Epub 2020 Jan 27.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg (C.P.d.C.G., Y.D.).

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012349PMC
January 2020

Epigenetic Signaling and RNA Regulation in Cardiovascular Diseases.

Int J Mol Sci 2020 Jan 13;21(2). Epub 2020 Jan 13.

Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 4, 27100 Pavia, Italy.

RNA epigenetics is perhaps the most recent field of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combinations whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes in RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.
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http://dx.doi.org/10.3390/ijms21020509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014325PMC
January 2020

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.

Int J Mol Sci 2019 Dec 24;21(1). Epub 2019 Dec 24.

Laboratory of Molecular Cardiology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, 20097 Milan, Italy.

Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210; for miR-210 gain-of-function, a doxycycline-inducible miR-210 transgenic mouse was used. We tested miR-210 ability to stimulate vascular regeneration following ischemia. We found that miR-210 was necessary and sufficient to stimulate blood perfusion recovery, as well as arteriolar and capillary density increase, in the ischemic muscle. To clarify the molecular events underpinning miR-210 pro-angiogenic action, the transcriptomic changes in ischemic muscles upon miR-210 blocking were analyzed. We found that miR-210 impacted the transcriptome significantly, regulating pathways and functions linked to vascular regeneration. In agreement with a pro-angiogenic role, miR-210 also improved cardiac function and left ventricular remodeling after myocardial infarction. Moreover, miR-210 blocking decreased capillary density in a Matrigel plug assay, indicating that miR-210 is necessary for angiogenesis independently of ischemia. Collectively, these data indicate that miR-210 plays a pivotal role in promoting vascular regeneration.
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http://dx.doi.org/10.3390/ijms21010129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981725PMC
December 2019

Long Noncoding Competing Endogenous RNA Networks in Age-Associated Cardiovascular Diseases.

Int J Mol Sci 2019 Jun 24;20(12). Epub 2019 Jun 24.

Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Cardiovascular diseases (CVDs) are the most serious health problem in the world, displaying high rates of morbidity and mortality. One of the main risk factors for CVDs is age. Indeed, several mechanisms are at play during aging, determining the functional decline of the cardiovascular system. Aging cells and tissues are characterized by diminished autophagy, causing the accumulation of damaged proteins and mitochondria, as well as by increased levels of oxidative stress, apoptosis, senescence and inflammation. These processes can induce a rapid deterioration of cellular quality-control systems. However, the molecular mechanisms of age-associated CVDs are only partially known, hampering the development of novel therapeutic strategies. Evidence has emerged indicating that noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and micro RNAs (miRNAs), are implicated in most patho-physiological mechanisms. Specifically, lncRNAs can bind miRNAs and act as competing endogenous-RNAs (ceRNAs), therefore modulating the levels of the mRNAs targeted by the sponged miRNA. These complex lncRNA/miRNA/mRNA networks, by regulating autophagy, apoptosis, necrosis, senescence and inflammation, play a crucial role in the development of age-dependent CVDs. In this review, the emerging knowledge on lncRNA/miRNA/mRNA networks will be summarized and the way in which they influence age-related CVDs development will be discussed.
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http://dx.doi.org/10.3390/ijms20123079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627372PMC
June 2019

The Dark That Matters: Long Non-coding RNAs as Master Regulators of Cellular Metabolism in Non-communicable Diseases.

Front Physiol 2019 22;10:369. Epub 2019 May 22.

Laboratory of Epigenetics, ICS Maugeri S.p.A., Pavia, Italy.

Non-coding RNAs are pivotal for many cellular functions, such as splicing, gene regulation, chromosome structure, and hormone-like activity. Here, we will report about the biology and the general molecular mechanisms associated with long non-coding RNAs (lncRNAs), a class of >200 nucleotides-long ribonucleic acid sequences, and their role in chronic non-transmissible diseases. In particular, we will summarize knowledge about some of the best-characterized lncRNAs, such as H19 and MALAT1, and how they regulate carbohydrate and lipid metabolism as well as protein synthesis and degradation. Evidence is discussed about how lncRNAs expression might affect cellular and organismal metabolism and whether their modulation could provide ground for the development of innovative treatments.
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http://dx.doi.org/10.3389/fphys.2019.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539782PMC
May 2019

Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1.

Int J Mol Sci 2019 Apr 19;20(8). Epub 2019 Apr 19.

Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by "back-splicing", which is the linking covalently of 3'- and 5'-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.
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http://dx.doi.org/10.3390/ijms20081938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515344PMC
April 2019

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129.

Noncoding RNA 2019 03 29;5(2). Epub 2019 Mar 29.

Research Unit of Biomedicine, University of Oulu, 90014 Oulu, Finland.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).
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http://dx.doi.org/10.3390/ncrna5020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630366PMC
March 2019

P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.

FASEB J 2019 03 10;33(3):4107-4123. Epub 2018 Dec 10.

Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri, Pavia, Italy.

The epigenetic enzyme p300/CBP-associated factor (PCAF) belongs to the GCN5-related N-acetyltransferase (GNAT) family together with GCN5. Although its transcriptional and post-translational function is well characterized, little is known about its properties as regulator of cell metabolism. Here, we report the mitochondrial localization of PCAF conferred by an 85 aa mitochondrial targeting sequence (MTS) at the N-terminal region of the protein. In mitochondria, one of the PCAF targets is the isocitrate dehydrogenase 2 (IDH2) acetylated at lysine 180. This PCAF-regulated post-translational modification might reduce IDH2 affinity for isocitrate as a result of a conformational shift involving predictively the tyrosine at position 179. Site-directed mutagenesis and functional studies indicate that PCAF regulates IDH2, acting at dual level during myoblast differentiation: at a transcriptional level together with MyoD, and at a post-translational level by direct modification of lysine acetylation in mitochondria. The latter event determines a decrease in IDH2 function with negative consequences on muscle fiber formation in C2C12 cells. Indeed, a MTS-deprived PCAF does not localize into mitochondria, remains enriched into the nucleus, and contributes to a significant increase of muscle-specific gene expression enhancing muscle differentiation. The role of PCAF in mitochondria is a novel finding shedding light on metabolic processes relevant to early muscle precursor differentiation.-Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Di Marcotullio, L., Botta, B., Martelli, F., Zeiher, A. M., Pontecorvi, A., Farsetti, A., Spallotta, F., Gaetano, C. P300/CBP-associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation.
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http://dx.doi.org/10.1096/fj.201800788RDOI Listing
March 2019

Circular RNAs in Muscle Function and Disease.

Int J Mol Sci 2018 Nov 3;19(11). Epub 2018 Nov 3.

Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Circular RNAs (circRNAs) are a class of RNA produced during pre-mRNA splicing that are emerging as new members of the gene regulatory network. In addition to being spliced in a linear fashion, exons of pre-mRNAs can be circularized by use of the 3' acceptor splice site of upstream exons, leading to the formation of circular RNA species. In this way, genetic information can be re-organized, increasing gene expression potential. Expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across eukaryotes. The importance of circRNAs in gene regulation is now beginning to be recognized and some putative functions have been assigned to them, such as the sequestration of microRNAs or proteins, the modulation of transcription, the interference with splicing, and translation of small proteins. In accordance with an important role in normal cell biology, circRNA deregulation has been reported to be associated with diseases. Recent evidence demonstrated that circRNAs are highly expressed in striated muscle tissue, both skeletal and cardiac, that is also one of the body tissue showing the highest levels of alternative splicing. Moreover, initial studies revealed altered circRNA expression in diseases involving striated muscle, suggesting important functions of these molecules in the pathogenetic mechanisms of both heart and skeletal muscle diseases. The recent findings in this field will be described and discussed.
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http://dx.doi.org/10.3390/ijms19113454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274904PMC
November 2018

Circular RNAs: Methodological challenges and perspectives in cardiovascular diseases.

J Cell Mol Med 2018 11 11;22(11):5176-5187. Epub 2018 Sep 11.

Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Milan, Italy.

Circular RNAs are generated by back-splicing of precursor-mRNAs. Although they have been known for many years, only recently we have started to appreciate their widespread expression and their regulatory functions in a variety of biological processes. Not surprisingly, circular RNA dysregulation and participation in the pathogenic mechanisms have started to emerge in many instances, including cardiovascular diseases. Detection, differential expression analysis and validation are the three critical points for the characterization of any RNA, and circular RNAs are no exception. Their characteristics, however, generate several problems that are yet to be completely addressed, and literature still lacks comprehensive definitions of well-defined best practices. We present a map of the current knowledge regarding circular RNAs and the critical issues limiting our understanding of their regulation and function. The goal was to provide the readers with the tools to critically decide which of the many approaches available is most suitable to their experimental plan. Although particularly focused on cardiovascular diseases, most critical issues concerning circular RNAs are common to many other fields of investigation.
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http://dx.doi.org/10.1111/jcmm.13789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201346PMC
November 2018

High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2.

Cell Death Dis 2018 06 28;9(7):729. Epub 2018 Jun 28.

Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by abnormally expanded stretches of CTG DNA triplets in the DMPK gene, leading to mutated-transcript RNA-toxicity. MicroRNAs (miRNAs) are short non-coding RNAs that, after maturation, are loaded onto the RISC effector complex that destabilizes target mRNAs and represses their translation. In DM1 muscle biopsies not only the expression, but also the intracellular localization of specific miRNAs is disrupted, leading to the dysregulation of the relevant mRNA targets. To investigate the functional alterations of the miRNA/target interactions in DM1, we analyzed by RNA-sequencing the RISC-associated RNAs in skeletal muscle biopsies derived from DM1 patients and matched controls. The mRNAs found deregulated in DM1 biopsies were involved in pathways and functions relevant for the disease, such as energetic metabolism, calcium signaling, muscle contraction and p53-dependent apoptosis. Bioinformatic analysis of the miRNA/mRNA interactions based on the RISC enrichment profiles, identified 24 miRNA/mRNA correlations. Following validation in 21 independent samples, we focused on the couple miR-29c/ASB2 because of the role of miR-29c in fibrosis (a feature of late-stage DM1 patients) and of ASB2 in the regulation of muscle mass. Luciferase reporter assay confirmed the direct interaction between miR-29c and ASB2. Moreover, decreased miR-29c and increased ASB2 levels were verified also in immortalized myogenic cells and primary fibroblasts, derived from biopsies of DM1 patients and controls. CRISPR/Cas9-mediated deletion of CTG expansions rescued normal miR-29c and ASB2 levels, indicating a direct link between the mutant repeats and the miRNA/target expression. In conclusion, functionally relevant miRNA/mRNA interactions were identified in skeletal muscles of DM1 patients, highlighting the dysfunction of miR-29c and ASB2.
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http://dx.doi.org/10.1038/s41419-018-0769-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023919PMC
June 2018

miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia.

Mol Ther 2018 07 15;26(7):1694-1705. Epub 2018 Jun 15.

Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy. Electronic address:

Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.
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http://dx.doi.org/10.1016/j.ymthe.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036333PMC
July 2018

A Breath of Fresh Air(n) in Molecular Cardiology: Long Noncoding RNA Regulates Cardiomyocyte Resistance to Stress and Igf2bp2 Translation.

Circ Res 2018 05;122(10):1321-1323

From the Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy.

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http://dx.doi.org/10.1161/CIRCRESAHA.118.312966DOI Listing
May 2018

Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells.

Nat Commun 2018 03 29;9(1):1281. Epub 2018 Mar 29.

Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.
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http://dx.doi.org/10.1038/s41467-018-03668-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876398PMC
March 2018

CRISPR/Cas9-Mediated Deletion of CTG Expansions Recovers Normal Phenotype in Myogenic Cells Derived from Myotonic Dystrophy 1 Patients.

Mol Ther Nucleic Acids 2017 Dec 14;9:337-348. Epub 2017 Oct 14.

Institute of Cell Biology and Neurobiology, National Research Council, Monterotondo, Rome, Italy. Electronic address:

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, characterized by progressive myopathy, myotonia, and multi-organ involvement. This dystrophy is an inherited autosomal dominant disease caused by a (CTG)n expansion within the 3' untranslated region of the DMPK gene. Expression of the mutated gene results in production of toxic transcripts that aggregate as nuclear foci and sequester RNA-binding proteins, resulting in mis-splicing of several transcripts, defective translation, and microRNA dysregulation. No effective therapy is yet available for treatment of the disease. In this study, myogenic cell models were generated from myotonic dystrophy patient-derived fibroblasts. These cells exhibit typical disease-associated ribonuclear aggregates, containing CUG repeats and muscleblind-like 1 protein, and alternative splicing alterations. We exploited these cell models to develop new gene therapy strategies aimed at eliminating the toxic mutant repeats. Using the CRISPR/Cas9 gene-editing system, the repeat expansions were removed, therefore preventing nuclear foci formation and splicing alterations. Compared with the previously reported strategies of inhibition/degradation of CUG expanded transcripts by various techniques, the advantage of this approach is that affected cells can be permanently reverted to a normal phenotype.
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http://dx.doi.org/10.1016/j.omtn.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684470PMC
December 2017

Central role of the p53 pathway in the noncoding-RNA response to oxidative stress.

Aging (Albany NY) 2017 12;9(12):2559-2586

Molecular Cardiology Laboratory, IRCCS Policlinico S. Donato, 20097, San Donato Milanese, Milan, Italy.

Oxidative stress plays a fundamental role in many conditions. Specifically, redox imbalance inhibits endothelial cell (EC) growth, inducing cell death and senescence. We used global transcriptome profiling to investigate the involvement of noncoding-RNAs in these phenotypes. By RNA-sequencing, transcriptome changes were analyzed in human ECs exposed to HO, highlighting a pivotal role of p53-signaling. Bioinformatic analysis and validation in p53-silenced ECs, identified several p53-targets among both mRNAs and long noncoding-RNAs (lncRNAs), including MALAT1 and NEAT1. Among microRNAs (miRNAs), miR-192-5p was the most induced by HO treatment, in a p53-dependent manner. Down-modulated mRNA-targets of miR-192-5p were involved in cell cycle, DNA repair and stress response. Accordingly, miR-192-5p overexpression significantly decreased EC proliferation, inducing cell death. A central role of the p53-pathway was also confirmed by the analysis of differential exon usage: Upon HO treatment, the expression of p53-dependent 5'-isoforms of MDM2 and PVT1 increased selectively. The transcriptomic alterations identified in HO-treated ECs were also observed in other physiological and pathological conditions where redox control plays a fundamental role, such as ECs undergoing replicative senescence, skeletal muscles of critical limb-ischemia patients and the peripheral-blood mononuclear cells of long-living individuals. Collectively, these findings indicate a prominent role of noncoding-RNAs in oxidative stress response.
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http://dx.doi.org/10.18632/aging.101341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764393PMC
December 2017