Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β

Padrón-Barthe, Laura; Villalba-Orero, María; Gómez-Salinero, Jesús M.; Domínguez, Fernándo; Roman, Marta Navarro; Larrasa-Alonso, Javier; Ortiz-Sánchez, Paula; Martínez, Fernando; López-Olañeta, Marina; Bonzón-Kulichenko, Elena; Vázquez, Jesús; Martí-Gómez, Carlos; Santiago, Demetrio J.; Prados, Belén; Giovinazzo, Giovanna; Gómez-Gaviro, Marı́a Victoria; Priori, Silvia G.; García‐Pavía, Pablo; Lara‐Pezzi, Enrique

doi:10.1161/circulationaha.119.040366

Cited by 67 publications

(90 citation statements)

References 42 publications

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“…Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a severe disease featured by an extensive fibrotic replacement. In animal models that recapitulate human ARVC, the cardiac fibrotic response was associated with an upregulation of Lox [83,84]. Finally, a strong induction of LOX was identified as the underlying cause of the restrictive cardiomyopathy evoked by a sustained running in SHR rats.…”

Section: Lox In Other Pathophysiological Settings Leading To Cardiac mentioning

confidence: 96%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1-4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter-and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. part of the mechanoresponsive gene programs responsible for the mechanical regulation of gene expression in cardiac myocytes and fibroblasts [11]. Thus, LOX/LOXLs contribute to cardiac fibrosis, but are also active players involved in the cellular mechanisms underlying cardiac dysfunction and disease progression.In the last years, multiple studies have contributed to the understanding of the pathophysiological role of the LOX family in human diseases and, in particular, in the cardiovascular system. The involvement of this family on vascular diseases has been recently reviewed [12]. Further, LOX/LOXLs participate in a variety of processes affecting the heart, from those associated to post-myocardial infarction (MI) cardiac remodeling, cardiac hypertrophy triggered by pressure or volume overload, heart failure (HF) with preserved ejection fraction (HFPEF) associated with obesity and metabolic syndrome or atrial fibrillation. The strong impact of the alteration of LOX/LOXLs on CCL and heart function supports the interest of these family of enzymes as pharmacological targets to improve cardiac remodeling and slow the progression to HF. In this review article we focus on those findings that support the fundamental involvement of the LOX family in the mechanisms underlying cardiac damage and repair. The LOX Family of ECM-Modifying EnzymesLOX is an extracellular enzyme which governs the post-translational modification of ECM collagen and elastin. LOX catalyzes the oxidative deamination of specific ε-amino groups of lysine and hydroxylysine residues in collagen and elastin. This leads to the generation of highly reactive peptidyl α-aminoadipic γ-semialdehydes and the release of hydrogen peroxide as by-product [1-3] (Figure 1). This reactio...

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Section: Lox In Other Pathophysiological Settings Leading To Cardiac mentioning

confidence: 96%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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“…A mouse model of ARVC subtype 5 expressing a mutated form of the non-desmosomal gene TMEM43 showed cardiomyocyte death and severe fibrofatty replacement. AKT was found inhibited, leading to GSK-3β activation and consequent inhibition of β-catenin activity in this mouse model [ 23 ]. Furthermore, the pathogenic role of inhibition of Wnt signaling in ACM has been shown in an ACM transgenic mouse model with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 with the Q558* nonsense mutation [ 20 ] and in a zebrafish model of DSP deficiency [ 21 ].…”

Section: Molecular Pathogenic Pathwaysmentioning

confidence: 99%

“…Several molecular and cellular mechanisms have been proposed to explain the pathogenesis of ACM. It has been shown that the presence of the ACM causal mutations induce activation of the Hippo signaling and inhibition of the Wnt signaling and activation of transforming growth factor beta (TGFβ) signaling [ 1 , 2 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Recent studies suggest electric instability in early stages of ACM may be the consequence of dysregulation of ion channels and Ca 2+ signaling machinery, not only as direct effect of causal mutations located in genes encoding components of the Ca 2+ homeostasis, but also as consequence of mutations in desmosomal genes [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

Gao

Puthenvedu

Lombardi

et al. 2020

IJMS

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Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

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“…The code for the simulations and the subsequent analysis of the data was conducted in Igor Pro. Electroporator Enhancer (22 pmol/each) were electroporated, and cells were recovered and split into p100 dishes as described (70). After 7-10 days, colonies were picked up and split into p96 and p24 well plates for screening and maintenance respectively.…”

Section: Monte Carlo Simulationsmentioning

confidence: 99%

“…One proved to be homozygous and another one heterozygous for the desired mutation. For cardiac differentiation, WT and TTN Cys3575Ser -hiPSC lines were expanded and dissociated into single cells as described (70). Briefly cells were seeded at a density of 1-1.2x10 6 cells per well in Essential E8 medium supplemented with 10 µM ROCK inhibitor.…”

Section: Monte Carlo Simulationsmentioning

confidence: 99%

Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

Herrero-Galán¹,

Domínguez

Martínez-Martín³

et al. 2020

Preprint

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The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants in TTN are currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice

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Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β

Abstract: Supplemental Digital Content is available in the text.

Cited by 67 publications

References 42 publications

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

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