Angeliki Asimaki1, Alexandros Protonotarios1, Cynthia A James1, Stephen P Chelko1, Crystal Tichnell1, Brittney Murray1, Adalena Tsatsopoulou1, Aris Anastasakis1, Anneline te Riele1, André G Kléber1, Daniel P Judge1, Hugh Calkins1, Jeffrey E Saffitz2. 1. From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis). 2. From the Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA (A. Asimaki, A.G.K., J.E.S.); Nikos Protonotarios Medical Center, Naxos, Greece (A.P., A.T.); Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (C.A.J., S.P.C., C.T., B.M., A.t.R., D.P.J., H.C.); and First Department of Cardiology, University of Athens Medical School, Athens, Greece (A. Anastasakis). jsaffitz@bidmc.harvard.edu.
Abstract
BACKGROUND: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells. METHODS AND RESULTS: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes. CONCLUSIONS: Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.
BACKGROUND: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells. METHODS AND RESULTS: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathypatients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes. CONCLUSIONS: Buccal mucosa cells from arrhythmogenic cardiomyopathypatients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.
Authors: Ashraf Al-Amoudi; Daniel Castaño-Diez; Damien P Devos; Robert B Russell; Graham T Johnson; Achilleas S Frangakis Journal: Proc Natl Acad Sci U S A Date: 2011-04-04 Impact factor: 11.205
Authors: Eduardo Garcia-Gras; Raffaella Lombardi; Michael J Giocondo; James T Willerson; Michael D Schneider; Dirar S Khoury; Ali J Marian Journal: J Clin Invest Date: 2006-07 Impact factor: 14.808
Authors: Angeliki Asimaki; Sudhir Kapoor; Eva Plovie; Anne Karin Arndt; Edward Adams; ZhenZhen Liu; Cynthia A James; Daniel P Judge; Hugh Calkins; Jared Churko; Joseph C Wu; Calum A MacRae; André G Kléber; Jeffrey E Saffitz Journal: Sci Transl Med Date: 2014-06-11 Impact factor: 17.956
Authors: Sachin A Shah; Christopher A Clyne; Nickole Henyan; Magdy Migeed; Ravi Yarlagadda; Burton B Silver; Jeffrey Kluger; C Michael White Journal: Conn Med Date: 2008-05
Authors: Liza S M Wong; Jardi Huzen; Rudolf A de Boer; Wiek H van Gilst; Dirk J van Veldhuisen; Pim van der Harst Journal: PLoS One Date: 2011-08-18 Impact factor: 3.240
Authors: Lee M Fidler; Gregory J Wilson; Fanfan Liu; Xuezhi Cui; Stephen W Scherer; Glenn P Taylor; Robert M Hamilton Journal: J Cell Mol Med Date: 2008-07-26 Impact factor: 5.310
Authors: Stephen P Chelko; Angeliki Asimaki; Justin Lowenthal; Carlos Bueno-Beti; Djahida Bedja; Arianna Scalco; Nuria Amat-Alarcon; Peter Andersen; Daniel P Judge; Leslie Tung; Jeffrey E Saffitz Journal: Circulation Date: 2019-09-19 Impact factor: 29.690
Authors: Babken Asatryan; Angeliki Asimaki; Andrew P Landstrom; Mohammed Y Khanji; Katja E Odening; Leslie T Cooper; Francis E Marchlinski; Anna R Gelzer; Christopher Semsarian; Tobias Reichlin; Anjali T Owens; C Anwar A Chahal Journal: Circulation Date: 2021-11-15 Impact factor: 39.918
Authors: Rene L Begay; Sharon L Graw; Gianfranco Sinagra; Angeliki Asimaki; Teisha J Rowland; Dobromir B Slavov; Katherine Gowan; Kenneth L Jones; Francesca Brun; Marco Merlo; Daniela Miani; Mary Sweet; Kalpana Devaraj; Eric P Wartchow; Marta Gigli; Ilaria Puggia; Ernesto E Salcedo; Deborah M Garrity; Amrut V Ambardekar; Peter Buttrick; T Brett Reece; Michael R Bristow; Jeffrey E Saffitz; Luisa Mestroni; Matthew R G Taylor Journal: JACC Clin Electrophysiol Date: 2018-02-02