Gianluigi Condorelli

University of Milan, Milano, Lombardy, Italy

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Publications (138)961.02 Total impact

  • Elena Cavarretta, Gianluigi Condorelli
    European Heart Journal 05/2015; DOI:10.1093/eurheartj/ehv184 · 14.72 Impact Factor
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    ABSTRACT: The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. To determine whether SMCs control EC functions through passage of miR-143 and miR-145. We used co-cultures of SMCs and ECs under different conditions as well as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another. Imaging of co-cultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we showed that miRNA passage is modulated by the transforming growth factor beta (TGFβ pathway, since both a specific TGFβ inhibitor (SB431542) and an shRNA against TGFβ RII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to form vessel-like structures when cultured on matrigel. We also identified hexokinase II (HKII) and integrin beta 8 (ITGβ8)-two genes essential for the angiogenic potential of ECs-as targets of miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype, similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex vivo and in vivo approaches, in which it was shown that TGFβ and vessel stress, respectively, triggered miR-143/145 transfer from SMCs to ECs. Our results demonstrate that miR-143 and miR-145 act as communication molecules between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs.
    Circulation Research 03/2015; 116(11). DOI:10.1161/CIRCRESAHA.116.305178 · 11.09 Impact Factor
  • Michael V G Latronico, Gianluigi Condorelli
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    ABSTRACT: In this review, we summarize the basic principles underlying the therapeutic use of nonprotein coding (nc)RNAs, such as microRNA (miRNA) and long noncoding RNA, in the cardiovascular field, focusing, where possible, on recent advances that may lead to translation to the clinic for heart failure. The number of individual miRNAs associated with a given aspect of heart disease is increasing rapidly, as is the data on miRNA profiles in normal and diseased myocardium. Less is known on the role of long noncoding RNA, and to date only a few have been studied in the heart. Novel oligonucleotide-based therapies have started to trickle into the clinic, but strategies focusing on ncRNA are still in a clinical/preclinical trial phase. The discovery of functional ncRNAs is leading to a better understanding of the mechanisms underlying cardiovascular physiology. Dysregulation of ncRNAs is being increasingly associated with many diseases affecting the heart and in certain instances may have a pathogenic role. Therapeutic intervention aimed at opposing ncRNA misexpression has been widely demonstrated to be effective in blunting disease in animal models, and may thus have potential in the clinical setting.
    Current Opinion in Cardiology 03/2015; 30(3). DOI:10.1097/HCO.0000000000000162 · 2.59 Impact Factor
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    ABSTRACT: Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.
  • Thomas Thum, Gianluigi Condorelli
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    ABSTRACT: RNAs not encoding proteins have gained prominence over the last couple of decades as fundamental regulators of cellular function. Not surprisingly, their dysregulation is increasingly being linked to pathology. Here, we review recent reports investigating the pathophysiological relevance of this species of RNA for the cardiovascular system, concentrating mainly on recent findings on long noncoding RNAs and microRNAs in cardiac hypertrophy and failure. © 2015 American Heart Association, Inc.
    Circulation Research 02/2015; 116(4):751-762. DOI:10.1161/CIRCRESAHA.116.303549 · 11.09 Impact Factor
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    ABSTRACT: Background Lone atrial flutter (AFL) and atrial fibrillation (AF) are common and sometimes consequential cardiac conduction disorders with a strong heritability, as underlined by recent genome-wide association studies that identified genetic modifiers. Follow-up family-based genetic analysis also identified Mendelian transmission of disease alleles. Three affected members were exome-sequenced for the identification of potential causative mutations, which were subsequently validated by direct sequencing in the other 3 affected members. Taqman assay was then used to confirm the role of any mutation in an independent population of sporadic lone AFL/AF cases. Results The family cluster analysis provided evidence of genetic inheritance of AFL in the family via autosomal dominant transmission. The exome-sequencing of 3 family members identified 7 potential mutations: of these, rs58238559, a rare missense genetic variant in the ATP-binding cassette sub-family B, member 4 (ABCB4) gene was carried by all affected members. Further analysis of 82 subjects with sporadic lone AF, 63 subjects with sporadic lone AFL, and 673 controls revealed that the allele frequency for this variation was significantly higher in cases than in the controls (0.05 vs. 0.01; OR = 3.73; 95% CI = 1.16–11.49; P = 0.013). Conclusions rs58238559 in ABCB4 is a rare missense variant with a significant effect on the development of AFL/AF. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0177-0) contains supplementary material, which is available to authorized users.
    BMC Genetics 02/2015; 2015(16):15. DOI:10.1186/s12863-015-0177-0 · 2.36 Impact Factor
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    ABSTRACT: LMNA/C mutations have been linked to the premature aging syndrome Hutchinson's progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype-phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies. DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members. In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype-phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB. Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.
    Immunity & Ageing 11/2014; 11(1). DOI:10.1186/s12979-014-0019-3 · 2.32 Impact Factor
  • Gianluigi Condorelli
    Journal of the American College of Cardiology 11/2014; 64(20). DOI:10.1016/j.jacc.2014.04.091 · 15.34 Impact Factor
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    ABSTRACT: Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.
    Cardiovascular Research 10/2014; DOI:10.1093/cvr/cvu225 · 5.81 Impact Factor
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    ABSTRACT: Background Exposure to subclinical levels of lipopolysaccharide (LPS) occurs commonly and is seemingly well tolerated. However, recurrent LPS exposure induces cardiac fibrosis over 2 to 3 months in a murine model, not mediated by the renin-angiotensin system. Subclinical LPS induces cardiac fibrosis by unique mechanisms. Methods In C57/Bl6 mice, LPS (10 mg/kg) or saline (control) were injected intraperitoneally once a week for 1–4 weeks. Mice showed no signs of distress, change in activity, appetite, or weight loss. Mice were euthanized after 3 days, 1, 2, or 4 weeks to measure cardiac expression of fibrosis-related genes and potential mediators (measured by QRT-PCR), including micro-RNA (miR) and NADPH oxidase (NOX). Collagen fraction area of the left ventricle was measured with picrosirius red staining. Cardiac fibroblasts isolated from adult mouse hearts were incubated with 0, 0.1, 1.0 or 10 ng/ml LPS for 48 hours. Results Cardiac miR expression profiling demonstrated decreased miR-29c after 3 and 7 days following LPS, which were confirmed by QRT-PCR. The earliest changes in fibrosis-related genes and mediators that occurred 3 days after LPS were increased cardiac expression of TIMP-1 and NOX-2 (but not of NOX-4). This persisted at 1 and 2 weeks, with additional increases in collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, TIMP2, and periostin. There was no change in TGF-β or connective tissue growth factor. Collagen fraction area of the left ventricle increased after 2 and 4 weeks of LPS. LPS decreased miR-29c and increased NOX-2 in isolated cardiac fibroblasts. Conclusions Recurrent exposure to subclinical LPS induces cardiac fibrosis after 2–4 weeks. Early changes 3 days after LPS were decreased miR-29c and increased NOX2 and TIMP1, which persisted at 1 and 2 weeks, along with widespread activation of fibrosis-related genes. Decreased miR-29c and increased NOX2, which induce cardiac fibrosis in other conditions, may uniquely mediate LPS-induced cardiac fibrosis.
    PLoS ONE 09/2014; 9(9):e107556. DOI:10.1371/journal.pone.0107556 · 3.53 Impact Factor
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  • M. Climent Salarich, G Condorelli, L Elia
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    ABSTRACT: Cardiometabolic diseases (CMD) are the primary cause of death and disability in the Western world. The recent developments in genetics and genomics provide a background for further investigating this area with the aim of deepening our understanding of the atherosclerotic phenomena underlying CMD. MicroRNAs (miRs) are short, non-coding RNAs that negatively regulate gene expression, and are involved in cardiovascular diseases. The cross talk between the different cell types of the vessel wall is fundamental in order to maintain the vessel integrity. This phenomenon is dysregulated during atherosclerosis development, inducing a modulation of smooth muscle cells (SMCs) and endothelial cells (ECs) biology. Methods/Results: The aim of this study is to understand whether the SMC-specific miR-143 and -145 might be transferred to ECs, then modulating their biological activity. Indeed, our data revealed that vascular stress is associated with down-regulation of miR-143 and -145 in SMCs: their modulation is responsible for SMC phenotypic switch from a contractile/non proliferative to a migratory/proliferative state. We observed that ECs, which do not normally express miR-143 and -145, do so after being co-cultured with SMCs, indicating that these miRs can be transferred from SMCs to ECs. ECs fed with SMC-conditioned media did not express miR-143 and -145. Instead, direct contact between the two cells types triggered the transfer of the miRs. This indicated that the transfer is not guided by any paracrine mechanism. Then, we observed that the transfer is restricted only to the mature miR sequences as no primary-miR-143/145 could be detected in ECs after co-culture.
    Cardiovascular Research 07/2014; 103(suppl 1):S49. DOI:10.1093/cvr/cvu084.3 · 5.81 Impact Factor
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    ABSTRACT: The miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Ldlr-/- and Ldlr-/--miR-143/145-/- (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. Experiments with the luciferase coding sequence fused to the ABCA1 3'UTR, Western blotting, qRT-PCR and mimicMiR confirmed the direct regulation of ABCA1 expression by miR-145. In conclusion, miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.
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    Gianluigi Condorelli, Michael V. G Latronico, Elena Cavarretta
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    ABSTRACT: Over the last few years, the field of microRNA (miRNA) in cardiovascular biology and disease has expanded at an incredible pace. miRNAs are themselves part of a larger family, that of non-coding RNAs, the importance of which for biological processes is starting to emerge. miRNAs are ∼22-nucleotide-long RNA sequences that can legate messenger (m)RNAs at partially complementary binding sites, and hence regulate the rate of protein synthesis by altering the stability of the targeted mRNAs. In the cardiovascular system, miRNAs have been shown to be critical regulators of development and physiology. They control basic functions in virtually all cell types relevant to the cardiovascular system (such as endothelial cells, cardiac muscle, smooth muscle, inflammatory cells, and fibroblasts) and, thus, are directly involved in the pathophysiology of many cardiovascular diseases. As a result of their role in disease, they are being studied for exploitation in diagnostics, prognostics, and therapeutics. However, there are still significant obstacles that need to be overcome before they enter the clinical arena. We present here a review of the literature and outline the directions toward their use in the clinic.
    Journal of the American College of Cardiology 06/2014; 63(21). DOI:10.1016/j.jacc.2014.01.050 · 15.34 Impact Factor
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    ABSTRACT: The morbidity and mortality from ischemic heart disease (IHD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of occluded coronary arteries. Although it is essential to re-open the artery as soon as possible, paradoxically this leads to additional myocardial injury, called acute ischemia-reperfusion injury (IRI), for which currently no effective therapy is available. Therefore, novel therapeutic strategies are required to protect the heart from acute IRI in order to reduce myocardial infarction size, preserve cardiac function and improve clinical outcomes in patients with IHD. In this review article, we will first outline the pathophysiology of acute IRI and review promising therapeutic strategies for cardioprotection. These include novel aspects of mitochondrial function, epigenetics, circadian clocks, the immune system, microvesicles, growth factors, stem cell therapy and gene therapy. We discuss the therapeutic potential of these novel cardioprotective strategies in terms of pharmacological targeting and clinical application.
    Pharmacology [?] Therapeutics 05/2014; 144(1). DOI:10.1016/j.pharmthera.2014.05.005 · 7.75 Impact Factor
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    ABSTRACT: RATIONALE: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, over-activation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors (βARs) in cardiomyocytes (CMs) and lead to increased heart rate and cardiac contractility. However, chronic stimulation of βARs leads to impaired cardiac function and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MiR-133 is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of mRNA translation/stability. OBJECTIVE: To determine whether miR-133 affects βAR signaling during progression to heart failure. METHODS AND RESULTS: Based on bioinformatic analysis, β1AR and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A (PKA), were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult CMs following selective β1AR stimulation. Furthermore, gain- and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model (Tg133). When subjected to transaortic constriction, Tg133 mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared to control mice. CONCLUSIONS: MiR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.
    Circulation Research 05/2014; · 11.09 Impact Factor
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    ABSTRACT: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, over-activation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors (βARs) in cardiomyocytes (CMs) and lead to increased heart rate and cardiac contractility. However, chronic stimulation of βARs leads to impaired cardiac function and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MiR-133 is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of mRNA translation/stability. To determine whether miR-133 affects βAR signaling during progression to heart failure. Based on bioinformatic analysis, β1AR and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A (PKA), were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult CMs following selective β1AR stimulation. Furthermore, gain- and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model (Tg133). When subjected to transaortic constriction, Tg133 mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared to control mice. MiR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.
    Circulation Research 05/2014; DOI:10.1161/CIRCRESAHA.115.303252 · 11.09 Impact Factor
  • JACC. Cardiovascular Interventions 04/2014; 7(4):448-9. DOI:10.1016/j.jcin.2014.01.154 · 7.44 Impact Factor
  • Journal of the American College of Cardiology 03/2014; · 15.34 Impact Factor
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    ABSTRACT: http://www.frontiersin.org/Journal/10.3389/fphys.2014.00015/abstract Atrial fibrillation (AF) is the most common sustained arrhythmia, especially in the elderly, and has a significant genetic component. Recently, several independent investigators have demonstrated a functional role for small non-coding RNAs (microRNAs) in the pathophysiology of this cardiac arrhythmia. This report represents a systematic and updated appraisal of the main studies that established a mechanistic association between specific microRNAs and AF, focusing both on the regulation of electrical and structural remodeling of cardiac tissue.
    Frontiers in Physiology 01/2014; 5:15. DOI:10.3389/fphys.2014.00015 · 3.50 Impact Factor

Publication Stats

5k Citations
961.02 Total Impact Points

Institutions

  • 2013–2015
    • University of Milan
      Milano, Lombardy, Italy
  • 2013–2014
    • Istituto Clinico Humanitas IRCCS
      Rozzano, Lombardy, Italy
  • 2009–2012
    • INO - Istituto Nazionale di Ottica
      Florens, Tuscany, Italy
  • 2008–2012
    • IRCCS Multimedica
      Milano, Lombardy, Italy
    • National Research Council
      • Institute of Biomedical Technologies ITB
      Oristany, Sardinia, Italy
  • 2005–2012
    • University of California, San Diego
      • • Department of Medicine
      • • Division of Cardiology
      San Diego, California, United States
  • 2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2008–2011
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
  • 2006–2011
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
    • Sapienza University of Rome
      Roma, Latium, Italy
    • The American University of Rome
      Roma, Latium, Italy
  • 2010
    • Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana
      Roma, Latium, Italy
  • 2008–2009
    • Norwegian University of Science and Technology
      • Department of Circulation and Medical Imaging
      Trondheim, Sor-Trondelag Fylke, Norway
  • 2002–2009
    • Thomas Jefferson University
      • • Kimmel Cancer Center
      • • Division of Cardiology
      Philadelphia, PA, United States
  • 2003–2007
    • Istituto Superiore di Sanità
      • Department of Haematology, Oncology and Molecular Medicine
      Roma, Latium, Italy
    • Università degli Studi di Salerno
      Fisciano, Campania, Italy
  • 2000–2005
    • University of Naples Federico II
      • • Department of Molecular Medicine and Health Biotechnology
      • • Department of Biology
      Napoli, Campania, Italy
    • IRCCS Istituto Neurologico Mediterraneo Neuromed
      Poczilli, Molise, Italy
  • 1997
    • Jefferson College
      Хиллсборо, Missouri, United States