Publications by authors named "Alexia Vite"

11 Publications

  • Page 1 of 1

Deficiency of bone morphogenetic protein-3b induces metabolic syndrome and increases adipogenesis.

Am J Physiol Endocrinol Metab 2020 08 30;319(2):E363-E375. Epub 2020 Jun 30.

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Bone morphogenetic protein (BMP) receptor signaling is critical for the regulation of the endocrine system and cardiovascular structure and function. The objective of this study was to investigate whether Bmp3b, a glycoprotein synthetized and secreted by adipose tissue, is necessary to regulate glucose and lipid metabolism, adipogenesis, and cardiovascular remodeling. Over the course of 4 mo, -knockout () mice gained more weight than wild-type (WT) mice. The plasma levels of cholesterol and triglycerides were higher in mice than in WT mice. mice developed insulin resistance and glucose intolerance. The basal heart rate was higher in mice than in WT mice, and echocardiography revealed eccentric remodeling in mice. The expression of adipogenesis-related genes in white adipose tissue was higher in mice than in WT control mice. In vitro studies showed that Bmp3b modulates the activity of the promoter, an effect mediated by Smad2/3. The results of this study suggest that Bmp3b is necessary for the maintenance of homeostasis in terms of age-related weight gain, glucose metabolism, and left ventricular (LV) remodeling and function. Interventions that increase the level or function of BMP3b may decrease cardiovascular risk and pathological cardiac remodeling.
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http://dx.doi.org/10.1152/ajpendo.00362.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473912PMC
August 2020

Desmoglein-2 mutations in propeptide cleavage-site causes arrhythmogenic right ventricular cardiomyopathy/dysplasia by impairing extracellular 1-dependent desmosomal interactions upon cellular stress.

Europace 2020 02;22(2):320-329

Sorbonne Université, Faculté de médecine Pitié-Salpêtrière, INSERM U1166, IHU ICAN, F-75013 Paris, France.

Aims: Desmoglein-2 (DSG2) mutations, which encode a heart-specific cadherin crucial for desmosomal adhesion, are frequent in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). DSG2 mutations have been associated with higher risk of biventricular involvement. Among DSG2 mutations, mutations of the inhibitory propeptide consensus cleavage-site (Arg-X-Arg/Lys-Arg), are particularly frequent. In the present work, we explored the functional consequences of DSG2 propeptide cleavage site mutations p.Arg49His, p.Arg46Trp, and p.Arg46Gln on localization, adhesive properties, and desmosome incorporation of DSG2.

Methods And Results: We studied the expression of mutant-DSG2 in human heart and in epithelial and cardiac cellular models expressing wild-type or mutant (p.Arg49His, p.Arg46Trp, and p.Arg46Gln) proDSG2-GFP fusion proteins. The consequences of the p.Arg46Trp mutation on DSG2 adhesiveness were studied by surface plasmon resonance. Incorporation of mutant p.Arg46Trp DSG2 into desmosomes was studied under low-calcium culture conditions and cyclic mechanical stress. We demonstrated in human heart and cellular models that all three mutations prevented N-terminal propeptide cleavage, but did not modify intercellular junction targeting. Surface plasmon resonance experiments showed a propeptide-dependent loss of interaction between the cadherin N-terminal extracellular 1 (EC1) domains. Additionally, proDSG2 mutant proteins were abnormally incorporated into desmosomes under low-calcium culture conditions or following mechanical stress. This was accompanied by an epidermal growth factor receptor-dependent internalization of proDSG2, suggesting increased turnover of unprocessed proDSG2.

Conclusion: Our results strongly suggest weakened desmosomal adhesiveness due to abnormal incorporation of uncleaved mutant proDSG2 in cellular stress conditions. These results provide new insights into desmosomal cadherin regulation and ARVC/D pathophysiology, in particular, the potential role of mechanical stress on desmosomal dysfunction.
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http://dx.doi.org/10.1093/europace/euz329DOI Listing
February 2020

Tunable and Reversible Substrate Stiffness Reveals a Dynamic Mechanosensitivity of Cardiomyocytes.

ACS Appl Mater Interfaces 2019 Jun 30;11(23):20603-20614. Epub 2019 May 30.

Department of Physics , Bryn Mawr College , Bryn Mawr , Pennsylvania 19010 , United States.

New directions in material applications have allowed for the fresh insight into the coordination of biophysical cues and regulators. Although the role of the mechanical microenvironment on cell responses and mechanics is often studied, most analyses only consider static environments and behavior, however, cells and tissues are themselves dynamic materials that adapt in myriad ways to alterations in their environment. Here, we introduce an approach, through the addition of magnetic inclusions into a soft poly(dimethylsiloxane) elastomer, to fabricate a substrate that can be stiffened nearly instantaneously in the presence of cells through the use of a magnetic gradient to investigate short-term cellular responses to dynamic stiffening or softening. This substrate allows us to observe time-dependent changes, such as spreading, stress fiber formation, Yes-associated protein translocation, and sarcomere organization. The identification of temporal dynamic changes on a short time scale suggests that this technology can be more broadly applied to study targeted mechanisms of diverse biologic processes, including cell division, differentiation, tissue repair, pathological adaptations, and cell-death pathways. Our method provides a unique in vitro platform for studying the dynamic cell behavior by better mimicking more complex and realistic microenvironments. This platform will be amenable to future studies aimed at elucidating the mechanisms underlying mechanical sensing and signaling that influence cellular behaviors and interactions.
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http://dx.doi.org/10.1021/acsami.9b02446DOI Listing
June 2019

Increased Afterload Augments Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model.

JACC Basic Transl Sci 2018 Apr 30;3(2):265-276. Epub 2018 May 30.

Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib.
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http://dx.doi.org/10.1016/j.jacbts.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059907PMC
April 2018

Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure.

Nat Med 2018 08 11;24(8):1225-1233. Epub 2018 Jun 11.

Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40-50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.
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http://dx.doi.org/10.1038/s41591-018-0046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195768PMC
August 2018

α-Catenin-dependent cytoskeletal tension controls Yap activity in the heart.

Development 2018 03 8;145(5). Epub 2018 Mar 8.

Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA

Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini, creating a specialized type of cell-cell contact called the intercalated disc (ICD). To investigate the relationship between ICD maturation and proliferation, αE-catenin () and αT-catenin () genes were deleted to generate cardiac-specific α-catenin double knockout (DKO) mice. DKO mice exhibited aberrant N-cadherin expression, mislocalized actomyosin activity and increased cardiomyocyte proliferation that was dependent on Yap activity. To assess effects on tension, cardiomyocytes were cultured on deformable polyacrylamide hydrogels of varying stiffness. When grown on a stiff substrate, DKO cardiomyocytes exhibited increased cell spreading, nuclear Yap and proliferation. A low dose of either a myosin or RhoA inhibitor was sufficient to block Yap accumulation in the nucleus. Finally, activation of RhoA was sufficient to increase nuclear Yap in wild-type cardiomyocytes. These data demonstrate that α-catenins regulate ICD maturation and actomyosin contractility, which, in turn, control Yap subcellular localization, thus providing an explanation for the loss of proliferative capacity in the newborn mammalian heart.
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http://dx.doi.org/10.1242/dev.149823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868989PMC
March 2018

New functions for alpha-catenins in health and disease: from cancer to heart regeneration.

Cell Tissue Res 2015 Jun 12;360(3):773-83. Epub 2015 Feb 12.

Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Suite 543E Jefferson Alumni Hall, 1020 Locust St., Philadelphia, PA, 19107, USA.

Strong cell-cell adhesion mediated by adherens junctions is dependent on anchoring the transmembrane cadherin molecule to the underlying actin cytoskeleton. To do this, the cadherin cytoplasmic domain interacts with catenin proteins, which include α-catenin that binds directly to filamentous actin. Originally thought to be a static structure, the connection between the cadherin/catenin adhesion complex and the actin cytoskeleton is now considered to be dynamic and responsive to both intercellular and intracellular signals. Alpha-catenins are mechanosensing proteins that undergo conformational change in response to cytoskeletal tension thus modifying the linkage between the cadherin and the actin cytoskeleton. There are three α-catenin isoforms expressed in mouse and human: αE-catenin (CTNNA1), αN-catenin (CTNNA2) and αT-catenin (CTNNA3). This review summarizes recent progress in understanding the in vivo function(s) of α-catenins in tissue morphogenesis, homeostasis and disease. The role of α-catenin in the regulation of cellular proliferation will be discussed in the context of cancer and regeneration.
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http://dx.doi.org/10.1007/s00441-015-2123-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456210PMC
June 2015

Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity.

Circ Res 2015 Jan 10;116(1):70-9. Epub 2014 Oct 10.

From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.

Rationale: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood.

Objective: To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout mice.

Methods And Results: We used 2 cardiac-specific Cre transgenes to delete both αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of α-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-catenin double knockout hearts. Fetal genes were increased in the α-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of α-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of α-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction.

Conclusions: These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration after injury.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.304472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282606PMC
January 2015

N-cadherin/catenin complex as a master regulator of intercalated disc function.

Cell Commun Adhes 2014 Jun 28;21(3):169-79. Epub 2014 Apr 28.

Department of Medicine, Center for Translational Medicine, Thomas Jefferson University , Philadelphia, PA , USA.

Intercellular adhesive junctions are essential for maintaining the physical integrity of tissues; this is particularly true for the heart that is under constant mechanical load. The correct functionality of the heart is dependent on the electrical and mechanical coordination of its constituent cardiomyocytes. The intercalated disc (ID) structure located at the termini of the rod-shaped adult cardiomyocyte contains various junctional proteins responsible for the integration of structural information and cell-cell communication. According to the classical description, the ID consists of three distinct junctional complexes: adherens junction (AJ), desmosome (Des), and gap junction (GJ) that work together to mediate mechanical and electrical coupling of cardiomyocytes. However, recent morphological and molecular studies indicate that AJ and Des components are capable of mixing together resulting in a "hybrid adhering junction" or "area composita." This review summarizes recent progress in understanding the in vivo function(s) of AJ components in cardiac homeostasis and disease.
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http://dx.doi.org/10.3109/15419061.2014.908853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054126PMC
June 2014

Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts.

PLoS One 2013 23;8(9):e75082. Epub 2013 Sep 23.

UPMC, University Paris 06, Hôpital Pitié-Salpêtrière, Paris, France ; INSERM, UMR_S956, ICAN, Hôpital Pitié-Salpêtrière, Paris, France.

Aims: Arrhythmogenic right ventricular Dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited cardiomyopathy associated with ventricular arrhythmia, heart failure and sudden death. Genetic studies have demonstrated the central role of desmosomal proteins in this disease, where 50% of patients harbor a mutation in a desmosmal gene. However, clinical diagnosis of the disease remains difficult and molecular mechanisms appears heterogeneous and poorly understood. The aim of this study was to characterize the expression profile of desmosomal proteins in explanted ARVD/C heart samples, in order to identify common features of the disease.

Methods And Results: We examined plakophilin-2, desmoglein-2, desmocollin-2, plakoglobin and β-catenin protein expression levels from seven independent ARVD/C heart samples compared to two ischemic, five dilated cardiomyopathy and one healthy heart sample as controls. Ventricular and septum sections were examined by immunoblot analysis of total heart protein extracts and by immunostaining. Immunoblots indicated significant decreases in desmoglein-2 and desmocollin-2, independent of any known underlying mutations, whereas immune-histochemical analysis showed normal localization of all desmosomal proteins. Quantitative RT-PCR revealed normal DSG2 and DSC2 mRNA transcript levels, suggesting increased protein turn-over rather than transcriptional down regulation.

Conclusion: Reduced cardiac desmoglein-2 and desmocollin-2 levels appear to be specifically associated with ARVD/C, independent of underlying mutations. These findings highlight a key role of desmosomal cadherins in the pathophysiology of ARVD/C. Whether these reductions could be considered as specific markers for ARVD/C requires replication analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075082PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781033PMC
July 2014

Screening of genes encoding junctional candidates in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Europace 2013 Oct 14;15(10):1522-5. Epub 2013 Jul 14.

UPMC Univ Paris 6, INSERM, UMRS 956, AP-HP, 91 Boulevard de l'Hôpital, Paris F-75013, France.

Aims: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by fibro-fatty replacement of the right ventricle and ventricular arrhythmias. The major disease-causing genes encode cardiac desmosomal components but are involved in only ∼50% of patients. To identify the missing genetic determinants, we used a candidate gene approach, focusing on the 3'-untranslated region (UTR) of the main ARVC/D gene PKP2 and on additional genes involved in desmosomal structure or function.

Methods And Results: We screened a population of 64 ARVC/D probands with no identified mutations in any of the five known desmosomal genes (PKP2, DSG2, DSP, DSC2, and JUP). No putative mutation was identified in the 3'-UTR of PKP2 or in PNN, CTNNA3, CAV1, or PLN coding sequences. In a single proband, we identified two rare heterozygous missense variants affecting evolutionary conserved residues: c.175G>A (p.Gly59Arg) in PERP and c.1811A>G (p.Asp604Gly) in PKP4 (minor allele frequency <0.5% in control population).

Conclusion: Our study suggests that mutations in the candidate genes studied and regulation of PKP2 mRNA via 3'-UTR dependent mechanisms are unlikely to be major causes of ARVC/D in the studied population. Additional studies are needed to investigate the putative effects of rare PKP4 and PERP variants in this disease.
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http://dx.doi.org/10.1093/europace/eut224DOI Listing
October 2013
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