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July 2021
Nature Communications
Beckert B, Leroy EC, Sothiselvam S, Bock LV, Svetlov MS, Graf M, Arenz S, Abdelshahid M, Seip B, Grubmüller H, Mankin AS, Innis CA, Vázquez-Laslop N, Wilson DN
July 2021
bioRxiv
Brás IC, Khani MH, Vasili E, Möbius W, Riedel D, Parfentev I, Gerhardt E, Fahlbusch C, Urlaub H, Zweckstetter M, Gollisch T, Outeiro TF
July 2021
BioRxiv
Hung KYS, Klumpe S, Eisele MR, Elsasser S, Tian G, Sun S, Moroco JA, Cheng TC, Joshi T, Seibel T, Van Dalen D, Feng XH, Lu Y, Ovaa H, Engen JR, Lee BH, Rudack T, Sakata E, Finley D
July 2021
American Journal of Physiology. Heart and Circulatory Physiology
Sadredini M, Haugsten Hansen M, Frisk M, Louch WE, Lehnart SE, Sjaastad I, Stokke MK
July 2021
Molecular Cell
Chen Y, Vos SM, Dienemann C, Ninov M, Urlaub H, Cramer P
July 2021
bioRxiv
Shahriyari M, Islam M, Sakib M, Rika A, Krueger D, Kaurani L, Anandakumar H, Shomroni O, Schmidt M, Salinas G, Unger A, Linke W, Zschuentzsch J, Schmidt J, Fischer A, Zimmermann W, Tiburcy M
July 2021
Genetics in Medicine
Iqbal M, Maroofian R, Çavdarlı B, Riccardi F, Field M, Banka S, Bubshait DK, Li Y, Hertecant J, Baig SM, Dyment D, Efthymiou S, Abdullah U, Makhdoom EUH, Ali Z, Scherf de Almeida T, Molinari F, Mignon-Ravix C, Chabrol B, Antony J, Ades L, Pagnamenta AT, Jackson A, Douzgou S; Genomics England Research Consortium, Beetz C, Karageorgou V, Vona B, Rad A, Baig JM, Sultan T, Alvi JR, Maqbool S, Rahman F, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Sarwar Y, Khan S, Jameel M, Noegel AA, Budde B, Altmüller J, Motameny S, Höhne W, Houlden H, Nürnberg P, Wollnik B, Villard L, Alkuraya FS, Osmond M, Hussain MS, Yigit G
July 2021
RNA Biology
Sievers K, Welp L, Urlaub H, Ficner R
July 2021
Biophysical Journal
Siegmund R, Werner F, Jakobs S, Geisler C, Egner A
July 2021
Cardiovascular Research
Rathjens FS, Blenkle A, Iyer LM, Renger A, Syeda F, Noack C, Jungmann A, Dewenter M, Toischer K, El-Armouche A, Müller OJ, Fabritz L, Zimmermann WH, Zelarayan LC, Zafeiriou MP

Authors

Rathjens FS, Blenkle A, Iyer LM, Renger A, Syeda F, Noack C, Jungmann A, Dewenter M, Toischer K, El-Armouche A, Müller OJ, Fabritz L, Zimmermann WH, Zelarayan LC, Zafeiriou MP

Journal

Cardiovascular Research

Citation

Cardiovasc Res. 2021 Jul 7;117(8):1908-1922.

Abstract

Aims 
Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.

Methods and results
We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced.

Conclusions 
This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.

DOI

10.1093/cvr/cvaa239

 
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