FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4306980861> ?p ?o ?g. }

• W4306980861 endingPage "1626" @default.
• W4306980861 startingPage "1610" @default.
• W4306980861 abstract "Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression.We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody.The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor-β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo.We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor-β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM." @default.
• W4306980861 created "2022-10-22" @default.
• W4306980861 creator A5001429864 @default.
• W4306980861 creator A5007014214 @default.
• W4306980861 creator A5008609896 @default.
• W4306980861 creator A5013827938 @default.
• W4306980861 creator A5017497597 @default.
• W4306980861 creator A5033029390 @default.
• W4306980861 creator A5037996724 @default.
• W4306980861 creator A5046560618 @default.
• W4306980861 creator A5056310967 @default.
• W4306980861 creator A5060596558 @default.
• W4306980861 creator A5063375035 @default.
• W4306980861 creator A5067692129 @default.
• W4306980861 creator A5069268241 @default.
• W4306980861 creator A5071402164 @default.
• W4306980861 creator A5081229617 @default.
• W4306980861 creator A5082085568 @default.
• W4306980861 creator A5083965570 @default.
• W4306980861 creator A5084072260 @default.
• W4306980861 date "2022-11-22" @default.
• W4306980861 modified "2023-10-01" @default.
• W4306980861 title "Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade" @default.
• W4306980861 cites W1548371304 @default.
• W4306980861 cites W1903803659 @default.
• W4306980861 cites W1968814354 @default.
• W4306980861 cites W1978545794 @default.
• W4306980861 cites W1995884865 @default.
• W4306980861 cites W2005545805 @default.
• W4306980861 cites W2010227280 @default.
• W4306980861 cites W2010457001 @default.
• W4306980861 cites W2051521992 @default.
• W4306980861 cites W2052192720 @default.
• W4306980861 cites W2059944258 @default.
• W4306980861 cites W2072728551 @default.
• W4306980861 cites W2079517510 @default.
• W4306980861 cites W2112195516 @default.
• W4306980861 cites W2116698038 @default.
• W4306980861 cites W2127904701 @default.
• W4306980861 cites W2136853458 @default.
• W4306980861 cites W2138207763 @default.
• W4306980861 cites W2140256258 @default.
• W4306980861 cites W2155139007 @default.
• W4306980861 cites W2165574770 @default.
• W4306980861 cites W2165882991 @default.
• W4306980861 cites W2167196315 @default.
• W4306980861 cites W2167774643 @default.
• W4306980861 cites W2169456326 @default.
• W4306980861 cites W2338497436 @default.
• W4306980861 cites W2341491381 @default.
• W4306980861 cites W2432757814 @default.
• W4306980861 cites W2544726413 @default.
• W4306980861 cites W2582355481 @default.
• W4306980861 cites W2782454362 @default.
• W4306980861 cites W2802113124 @default.
• W4306980861 cites W2803479625 @default.
• W4306980861 cites W2887191177 @default.
• W4306980861 cites W2941565518 @default.
• W4306980861 cites W2950056411 @default.
• W4306980861 cites W2972255324 @default.
• W4306980861 cites W2996279035 @default.
• W4306980861 cites W2997732843 @default.
• W4306980861 cites W3009875259 @default.
• W4306980861 cites W3014866787 @default.
• W4306980861 cites W3022047361 @default.
• W4306980861 cites W3035017768 @default.
• W4306980861 cites W3035912185 @default.
• W4306980861 cites W3041779359 @default.
• W4306980861 cites W3087286534 @default.
• W4306980861 cites W4200145823 @default.
• W4306980861 cites W4232058283 @default.
• W4306980861 doi "https://doi.org/10.1161/circulationaha.121.057329" @default.
• W4306980861 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36268721" @default.
• W4306980861 hasPublicationYear "2022" @default.
• W4306980861 type Work @default.
• W4306980861 citedByCount "5" @default.
• W4306980861 countsByYear W43069808612023 @default.
• W4306980861 crossrefType "journal-article" @default.
• W4306980861 hasAuthorship W4306980861A5001429864 @default.
• W4306980861 hasAuthorship W4306980861A5007014214 @default.
• W4306980861 hasAuthorship W4306980861A5008609896 @default.
• W4306980861 hasAuthorship W4306980861A5013827938 @default.
• W4306980861 hasAuthorship W4306980861A5017497597 @default.
• W4306980861 hasAuthorship W4306980861A5033029390 @default.
• W4306980861 hasAuthorship W4306980861A5037996724 @default.
• W4306980861 hasAuthorship W4306980861A5046560618 @default.
• W4306980861 hasAuthorship W4306980861A5056310967 @default.
• W4306980861 hasAuthorship W4306980861A5060596558 @default.
• W4306980861 hasAuthorship W4306980861A5063375035 @default.
• W4306980861 hasAuthorship W4306980861A5067692129 @default.
• W4306980861 hasAuthorship W4306980861A5069268241 @default.
• W4306980861 hasAuthorship W4306980861A5071402164 @default.
• W4306980861 hasAuthorship W4306980861A5081229617 @default.
• W4306980861 hasAuthorship W4306980861A5082085568 @default.
• W4306980861 hasAuthorship W4306980861A5083965570 @default.
• W4306980861 hasAuthorship W4306980861A5084072260 @default.
• W4306980861 hasBestOaLocation W43069808611 @default.
• W4306980861 hasConcept C126322002 @default.

• next