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Cited by 48Cardiovascular Effects of ExerciseCardiomyopathy and Myosin StudiesCardiac electrophysiology and arrhythmias

TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy

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Zheng, Guoxing, Jiang, Changying, Li, Yulin, Yang, Dandan, Ma, Youcai, Zhang, Bing, Li, Xuan, Zhang, Pei +4 more·2019·Protein & Cell
DOI 10.1007/s13238-018-0563-2PMC PMC6340891
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Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor κB (NF-κB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFβ1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.

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  • Crosstalk between inflammatory pathways and TGF-β may explain the heterogeneous patchiness of fibro-fatty replacement.

    “Crosstalk between inflammatory pathways and TGF-β may explain the heterogeneous patchiness of fibro-fatty replacement [86].”

    From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [86]

    The Discussion (page unavailable) reports that NF-κB activation induces TGF-β signaling and promotes cardiac fibrosis in TMEM43-S358L mice. The Results (page unavailable) also report increased fibrosis and fat accumulation, but the paper does not link this signaling to the heterogeneous patchiness of fibro-fatty replacement. It further notes that NF-κB activation did not produce a typical inflammatory response in these mice. (LLM, conf=0.86)

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Research works printed but not linked: 39

  1. Asimaki A Tandri H Duffy ER Winterfield JR Mackey-Bojack S Picken MM Cooper LT Wilber DJ Marcus FI Basso C Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy Circ Arrhythm Electrophysiol 2011 4 743 752 10.1161/CIRCEP.111.964890 21859801 PMC3203520 · DOI · Paper page
  2. Baskin B Skinner JR Sanatani S Terespolsky D Krahn AD Ray PN Scherer SW Hamilton RM TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations Hum Genet 2013 132 1245 1252 10.1007/s00439-013-1323-2 23812740 · DOI
  3. Bengtsson L Otto H LUMA interacts with emerin and influences its distribution at the inner nuclear membrane J Cell Sci 2008 121 536 548 10.1242/jcs.019281 18230648 · DOI
  4. Campian ME Verberne HJ Hardziyenka M de Groot EA van Moerkerken AF van Eck-Smit BL Tan HL Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia Eur J Nucl Med Mol Imaging 2010 37 2079 2085 10.1007/s00259-010-1525-y 20603720 PMC2948173 · DOI
  5. Campuzano O Alcalde M Iglesias A Barahona-Dussault C Sarquella-Brugada G Benito B Arzamendi D Flores J Leung TK Talajic M Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation J Clin Pathol 2012 65 1077 1083 10.1136/jclinpath-2012-201022 22944624 · DOI · Paper page
  6. Capulzini L Brugada P Brugada J Brugada R Arrhythmia and right heart disease: from genetic basis to clinical practice Rev Esp Cardiol 2010 63 963 983 10.1016/S0300-8932(10)70208-6 20738941 · DOI
  7. Chavez E Castro-Sanchez L Shibayama M Tsutsumi V Moreno MG Muriel P Sulfasalazine prevents the increase in TGF-beta, COX-2, nuclear NFkappaB translocation and fibrosis in CCl4-induced liver cirrhosis in the rat Hum Exp Toxicol 2012 31 913 920 10.1177/0960327112438928 22381741 · DOI
  8. Christensen AH Andersen CB Tybjaerg-Hansen A Haunso S Svendsen JH Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy Clin Genet 2011 80 256 264 10.1111/j.1399-0004.2011.01623.x 21214875 · DOI
  9. Grabiner BC Blonska M Lin PC You Y Wang D Sun J Darnay BG Dong C Lin X CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation Genes Dev 2007 21 984 996 10.1101/gad.1502507 17438001 PMC1847715 · DOI
  10. Hayden MS Ghosh S Signaling to NF-kappaB Genes Dev 2004 18 2195 2224 10.1101/gad.1228704 15371334 · DOI · Paper page
  11. Hayden MS Ghosh S Shared principles in NF-kappaB signaling Cell 2008 132 344 362 10.1016/j.cell.2008.01.020 18267068 · DOI
  12. Haywood AF Merner ND Hodgkinson KA Houston J Syrris P Booth V Connors S Pantazis A Quarta G Elliott P Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada Eur Heart J 2013 34 1002 1011 10.1093/eurheartj/ehs383 23161701 · DOI
  13. Hodgkinson KA Connors SP Merner N Haywood A Young TL McKenna WJ Gallagher B Curtis F Bassett AS Parfrey PS The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p. S358L mutation in TMEM43 Clin Genet 2013 83 321 331 10.1111/j.1399-0004.2012.01919.x 22725725 · DOI
  14. Jiang C Lin X Regulation of NF-kappaB by the CARD proteins Immunol Rev 2012 246 141 153 10.1111/j.1600-065X.2012.01110.x 22435552 PMC3339759 · DOI
  15. Jiang C Zhu Y Zhou Z Gumin J Bengtsson L Wu W Songyang Z Lang FF Lin X TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-kappaB activation and tumor progression Oncogene 2016 36 2813 10.1038/onc.2016.430 27991920 · DOI
  16. Klemm S Zimmermann S Peschel C Mak TW Ruland J Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production Proc Natl Acad Sci USA 2007 104 134 138 10.1073/pnas.0608388103 17095601 PMC1765423 · DOI
  17. Lakso M Pichel JG Gorman JR Sauer B Okamoto Y Lee E Alt FW Westphal H Efficient in vivo manipulation of mouse genomic sequences at the zygote stage Proc Natl Acad Sci USA 1996 93 5860 5865 10.1073/pnas.93.12.5860 8650183 PMC39152 · DOI · Paper page
  18. Li J Swope D Raess N Cheng L Muller EJ Radice GL Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling Mol Cell Biol 2011 31 1134 1144 10.1128/MCB.01025-10 21245375 PMC3067899 · DOI
  19. Lombardi R da Graca Cabreira-Hansen M Bell A Fromm RR Willerson JT Marian AJ Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy Circ Res 2011 109 1342 1353 10.1161/CIRCRESAHA.111.255075 22021931 PMC3237769 · DOI
  20. Maass DL White J Horton JW Nitric oxide donors alter cardiomyocyte cytokine secretion and cardiac function Crit Care Med 2005 33 2794 2803 10.1097/01.CCM.0000189747.97541.59 16352962 · DOI
  21. McAllister-Lucas LM Ruland J Siu K Jin X Gu S Kim DS Kuffa P Kohrt D Mak TW Nunez G CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells Proc Natl Acad Sci USA 2007 104 139 144 10.1073/pnas.0601947103 17101977 PMC1766317 · DOI
  22. Meng XM Nikolic-Paterson DJ Lan HY TGF-beta: the master regulator of fibrosis Nat Rev Nephrol 2016 12 325 338 10.1038/nrneph.2016.48 27108839 · DOI · Paper page
  23. Merner ND Hodgkinson KA Haywood AF Connors S French VM Drenckhahn JD Kupprion C Ramadanova K Thierfelder L McKenna W Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene Am J Hum Genet 2008 82 809 821 10.1016/j.ajhg.2008.01.010 18313022 PMC2427209 · DOI
  24. Milting H Klauke B Christensen AH Musebeck J Walhorn V Grannemann S Munnich T Saric T Rasmussen TB Jensen HK The TMEM43 Newfoundland mutation p. S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus Eur Heart J. 2015 36 872 881 10.1093/eurheartj/ehu077 24598986 · DOI
  25. Muthappan P Calkins H Arrhythmogenic right ventricular dysplasia Prog Cardiovasc Dis 2008 51 31 43 10.1016/j.pcad.2008.01.002 18634916 · DOI
  26. Niederbichler AD Westfall MV Su GL Donnerberg J Usman A Vogt PM Ipaktchi KR Arbabi S Wang SC Hemmila MR Cardiomyocyte function after burn injury and lipopolysaccharide exposure: single-cell contraction analysis and cytokine secretion profile Shock 2006 25 176 183 10.1097/01.shk.0000192123.91166.e1 16525357 · DOI
  27. Pan D Lin X Epithelial growth factor receptor-activated nuclear factor kappaB signaling and its role in epithelial growth factor receptor-associated tumors Cancer J 2013 19 461 467 10.1097/PPO.0000000000000001 24270344 · DOI
  28. Park KS Catalpol reduces the production of inflammatory mediators via PPAR-gamma activation in human intestinal Caco-2 cells J Nat Med 2016 70 620 626 10.1007/s11418-016-0988-y 27007911 · DOI
  29. Pilichou K Bezzina CR Thiene G Basso C Arrhythmogenic cardiomyopathy: transgenic animal models provide novel insights into disease pathobiology Circ Cardiovasc Genet 2011 4 318 326 10.1161/CIRCGENETICS.110.959031 21673311 · DOI
  30. Schirmer EC Florens L Guan T Yates JR III Gerace L Nuclear membrane proteins with potential disease links found by subtractive proteomics Science 2003 301 1380 1382 10.1126/science.1088176 12958361 · DOI
  31. Shambharkar PB Blonska M Pappu BP Li H You Y Sakurai H Darnay BG Hara H Penninger J Lin X Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways EMBO J 2007 26 1794 1805 10.1038/sj.emboj.7601622 17363905 PMC1847656 · DOI
  32. Uitto J Kouba D Cytokine modulation of extracellular matrix gene expression: relevance to fibrotic skin diseases J Dermatol Sci 2000 24 Suppl 1 S60 S69 10.1016/S0923-1811(00)00143-2 11137398 · DOI
  33. Verrecchia F Mauviel A Transforming growth factor-beta and fibrosis World J Gastroenterol 2007 13 3056 3062 10.3748/wjg.v13.i22.3056 17589920 PMC4172611 · DOI
  34. Wada K Kamisaki Y Anti-inflammatory effect of PPARgamma agonists: basics and clinical applications Nihon Rinsho 2010 68 278 283 20158097
  35. Wang D You Y Lin PC Xue L Morris SW Zeng H Wen R Lin X Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors Proc Natl Acad Sci USA 2007 104 145 150 10.1073/pnas.0601894104 17179215 PMC1765424 · DOI
  36. Weber KT Sun Y Bhattacharya SK Ahokas RA Gerling IC Myofibroblast-mediated mechanisms of pathological remodelling of the heart Nat Rev Cardiol 2013 10 15 26 10.1038/nrcardio.2012.158 23207731 · DOI
  37. Xu F Liu C Zhou D Zhang L TGF-beta/SMAD pathway and its regulation in hepatic fibrosis J Histochem Cytochem 2016 64 157 167 10.1369/0022155415627681 26747705 PMC4810800 · DOI
  38. Zhang M Guo Y Fu H Hu S Pan J Wang Y Cheng J Song J Yu Q Zhang S Chop deficiency prevents UUO-induced renal fibrosis by attenuating fibrotic signals originated from Hmgb1/TLR4/NFkappaB/IL-1beta signaling Cell Death Dis 2015 6 e1847 10.1038/cddis.2015.206 26247732 PMC4558499 · DOI
  39. Zhou J Liang Y Pan JX Wang FF Lin XM Ma RJ Qu F Fang JQ Protein extracts of Crassostrea gigas alleviate CCl(4)-induced hepatic fibrosis in rats by reducing the expression of CTGF, TGF-beta1 and NF-kappaB in liver tissues Mol Med Rep 2015 11 2913 2920 10.3892/mmr.2014.3019 25434425 · DOI

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Authors
Zheng, G., Jiang, C., Li, Y., Yang, D., Ma, Y., Zhang, B., Li, X., Zhang, P., Hu, X., Zhao, X., Du, J., & Lin, X.
Affiliations
  • Sun Yat-sen University (CN)
  • The University of Texas MD Anderson Cancer Center (US)
  • Capital Medical University (CN)
  • Tsinghua University (CN)
  • Peking University (CN)
Corresponding author
  • Zheng, Guoxing
  • Lin, Xin
ORCID
Venue
Protein & Cell
Publisher
Oxford University Press (OUP)
Published
2018-07-06
Volume
10
Issue
2
Pages
104-119
ISSN
  • 1674-800X (ISSN-L)
  • 1674-8018
DOI
10.1007/s13238-018-0563-2
PMC
PMC6340891
OpenAlex
W2831567692
Cited by
48
References
2
Citations by year
2026: 3 · 2025: 9 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 6 · 2019: 2
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Protein & Cell (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
  • National Natural Science Foundation of China (81570211)
  • China Postdoctoral Science Foundation
  • Tsinghua University
  • University of Texas MD Anderson Cancer Center
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
arrhythmogenic right ventricular cardiomyopathy, TMEM43, NF-κB activation, TGF-β1, myocardial fibrosis, sudden cardiac death, mouse model, genetic cardiac disease
MeSH terms
Animals, Cell Line, Humans, Membrane Proteins, Mice, Inbred C57BL, Mutation, NF-kappa B, Arrhythmogenic Right Ventricular Dysplasia, Genetic Predisposition to Disease, Mice, Transforming Growth Factor beta1

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