Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes
Abstract
:1. Introduction
2. Intercalated Discs
3. Murine Models for ACM Associated with Plakophilin 2 Variants
Gene | Experimental Model | Alterations | Refs. |
---|---|---|---|
Pkp2 | Pkp2 homozygous-null embryos | Mislocation of desmosomal proteins Altered organization of cardiac junctions | [22] |
Pkp2 heterozygous-null mice | Reduced number of mechanical junctions Reduced intercellular distances in correspondence of IDs Upregulation of ECM components ↑TGF-β1/p38 MAPK pathway Desmosomes sporadic or absent Expanded space between cardiomyocytes Ventricular arrhythmias | [23,24,25] | |
Cardiomyocyte-specific Pkp2 conditional KO | Right ventricle dysfunction Arrhythmias Cardiac fibrosis Increased calcium concentration Enhanced frequency of spontaneous calcium release events measured in vitro | [26,27] | |
Complete Pkp2 knock-down via shRNA | Enlarged left ventricle Interstitial fibrosis Presence of cells with lipid droplets | [36] | |
Tg mice with cardiomyocyte-specific overexpression of PKP2 with p.R375* variation | Right ventricle dysfunction exacerbated by training Altered localization and distribution of CX43 | [29] | |
Tg mice with cardiomyocyte-specific overexpression of PKP2 with p.S329* variation | Ventricular arrhythmias Reduced left ventricle systolic function Reduced expression of proteins CX43 and NaV1.5 Downregulation of junctional proteins expression | [30] | |
Pkp2 heterozygous KI mice with c.1086InsT variation | Reduced right ventricle functionality Increased apoptotic cardiomyocytes Increased widening of intercalated discs | [32] | |
Pkp2 heterozygous KI mice with c.1755delA variation | Cardiac fibrosis Reduced expression of junctional proteins Increased width of IDs | [33] | |
Pkp2 homozygous KI mice | Alterations in sodium current Loss of Nav1.5 subunit Enlarged ventricles Cardiac fibrosis Subepicardial adiposis Reduced number of desmosomes Reduced expression of junctional proteins | [34] |
4. Murine Models for ACM Associated with Desmoplakin Variants
Gene | Experimental Model | Alterations | Refs. |
---|---|---|---|
Dsp | General Dsp KO mice | Embryonic lethality | [38] |
Cardiomyocyte-specific Dsp deficient mice | High embryonic lethality in Dsp−/− mice Molecular remodeling of IDs Fibro-fatty replacement LV dilation Reduced fractional shortening Nuclear localization of plakoglobin ↑ Adipogenesis and fibrogenesis ↓ Wnt/β-catenin signaling ↑ Hippo pathway ↑ Inflammation and EMT-related genes ↓ Oxidative phosphorylation-related genes | [39,40,42] | |
Cardiomyocyte-specific Dsp KO mice | Structural defects in desmosomal integrity Cardiac cells death Fibro-fatty replacement Ventricular arrhythmias exacerbated with exercise or catecholamine stimulation ↓ CX40 protein level ↓CX43 protein level | [43] | |
Mice with conditional heterozygous Dsp deletion in cFAPs | Increased fibro-adipogenesis Mild cardiac dysfunction ↓ Wnt/β-catenin signaling ↑ Adipogenesis in cFAPs | [44] | |
Tg mice with cardiomyocyte-specific overexpression of DSP with p.R3834H variation | Increased cardiomyocytes apoptosis Cardiac fibrosis and lipid accumulations Ultrastructural alterations of IDs Cardiac hypertrophy ↑ PKP2 and β-catenin Accelerated ACM pathogenesis when exposed to endurance exercise ↓ Wnt/β-catenin signaling when exposed to endurance exercise | [45,49] | |
Dsp KI mice | Embryonic lethality in Dsp R451G/R451G Aberrant CX43 localization Stress-induced arrhythmias Accelerated heart failure following pressure overload | [51] |
5. Murine Models for ACM Associated with Desmoglein 2 Variants
Gene | Experimental Model | Alterations | Refs. |
---|---|---|---|
Dsg2 | Dsg2 KO mice lacking exons 7–8 | Embryonic lethality | [53] |
Dsg2 KO mice lacking exons 4–6 | Cardiac fibrosis Inflammatory infiltrates Ventricular dilation Arrhythmias and cardiac insufficiency | [54,55] | |
Cardiomyocyte-specific Dsg2 KO mice lacking exons 4–6 | Aberrant CX43 localization Cardiomyocyte necrosis Cardiac fibrosis Functional alterations | [56] | |
Dsg2 KO mice lacking exons 4–5 | Abnormal localization of junctional proteins Cardiac fibrosis Inflammation GSK3β constitutive activation ↑ NFkB signaling pathway | [57,61,62] | |
Dsg2 KI mice | Wide IDs Cardiac fibrosis Echocardiography and ECG abnormalities ↑ TGF-β signaling pathway | [64] | |
Tg mice with cardiomyocyte-specific overexpression of DSG2 with p.N271S variation | Cardiac fibrosis Ventricular dilation Cardiac dysfunction Ventricular arrhythmias | [65,68] | |
Tg mice with cardiomyocyte-specific overexpression of human DSG2 with p.Q558* variation | Decrease in size and number of desmosomes Cardiac fibrosis ↓ Wnt signaling | [66] | |
Cardiomyocyte-specific Dsg2 null mice | Lipid accumulation Cardiac fibrosis Ventricular dilation Impaired contractile function ↓ PPARα ↓ mTOR-4EBP1 axis ↑ TGF-β signaling pathway | [71,72] |
6. Murine Models for ACM-Associated Desmocollin 2 Variants
Gene | Experimental Model | Alterations | Refs. |
---|---|---|---|
Dsc2 | Dsc2 KI mice | No structural and functional defects Slight LV dilation in homozygous G790del mice Aberrant Ca2+ release in homozygous G790del mice | [75] |
Tg mice with cardiomyocyte-specific overexpression of WT DSC2 | Myocardial necrosis Fibrotic replacement Severe cardiac dysfunction | [76] |
7. Murine Models for ACM Associated with Plakoglobin Variants
Gene | Experimental Model | Alterations | Refs. |
---|---|---|---|
Jup | Homozygous Jup KO embryos | Less developed heart Thin cardiac walls Reduced number of cardiac desmosomes | [81] |
Heterozygous Jup KO mice | Right ventricle dilatation and dysfunction exacerbated with exercise Ventricular arrhythmias exacerbated with exercise Low concentration of CX43 protein | [82,83] | |
Cardiomyocyte-specific Jup KO mice lacking exons 3–5 | Enlarged hearts Right ventricle dilatation Hypertrophic cardiomyocytes Enhanced apoptosis of cardiomyocytes Cardiac fibrosis Absence of normal desmosomes ↑ TGF-β pathway | [84] | |
Cardiomyocyte-specific Jup KO mice lacking exon 1 | Cardiac dilatation Cardiac fibrosis Reduced levels of DSG2 protein at intercalated discs Abrogation of positive effects of β-adrenergic signaling | [85] | |
Cardiomyocyte-specific Jup conditional KO mice | Enlarged ventricles Focal areas of cardiomyocyte loss Inflammatory infiltrates Cardiac fibrosis Reduced junctional proteins expression at the intercalated discs Reduced CX43-containing gap junction plaques Reduction in the number and length of desmosomes ↑ β-catenin ↑ Myc and Fos ↑ c-MYC ↓ GSK3β ↑ Wnt/β-catenin signaling | [86] | |
Cardiomyocyte-specific Jup and Ctnnb1 conditional KO mice | Enlarged ventricles Increased number of apoptotic cells Fibroblasts interspersed through myocardium Collagen deposition Reduced junctional proteins levels Decreased area occupied by gap junction plaques Loss of IDs structures | [87] | |
Tg mice with cardiomyocyte-specific overexpression of Flag-tagged PG | Cardiac fibrosis and adiposis ↓ Wnt/β-catenin signaling | [88] | |
Tg mice with cardiomyocyte-specific overexpression of truncated or wild-type PG | Cardiac fibrosis and adiposis Enhanced adipogenesis in cardiac progenitor cells Molecular remodeling of IDs Nuclear localization of plakoglobin ↓ Wnt/β-catenin signaling ↑ Hippo pathway Abnormal localization of junctional proteins Inflammatory infiltrates | [40,57,90] |
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Vencato, S.; Romanato, C.; Rampazzo, A.; Calore, M. Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes. Int. J. Mol. Sci. 2024, 25, 6208. https://doi.org/10.3390/ijms25116208
Vencato S, Romanato C, Rampazzo A, Calore M. Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes. International Journal of Molecular Sciences. 2024; 25(11):6208. https://doi.org/10.3390/ijms25116208
Chicago/Turabian StyleVencato, Sara, Chiara Romanato, Alessandra Rampazzo, and Martina Calore. 2024. "Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes" International Journal of Molecular Sciences 25, no. 11: 6208. https://doi.org/10.3390/ijms25116208