Overexpression of Cx43 in Cells of the Myocardial Scar: Correction of Post-infarct Arrhythmias Through Heterotypic Cell-cell Coupling

Overview

Journal Sci Rep

Specialty Science

Date 2018 May 10

PMID 29739982

Citations 21

Authors

Wilhelm Roell

Alexandra M Klein

Martin Breitbach

Torsten S Becker

Ashish Parikh

Jane Lee

Katrin Zimmermann

Shaun Reining

Beth Gabris

Annika Ottersbach

Robert Doran

Britta Engelbrecht

Miriam Schiffer

Kenichi Kimura

Patricia Freitag

Esther Carls

Caroline Geisen

Georg D Duerr

Philipp Sasse

Armin Welz

Alexander Pfeifer

Guy Salama

Michael Kotlikoff

Bernd K Fleischmann

Affiliations

Soon will be listed here.

Abstract

Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). Biological correction of the conduction inhomogeneity that underlies re-entry could be a major advance in infarction therapy. As minimal increases in conduction of infarcted tissue markedly influence VT susceptibility, we reasoned that enhanced propagation of the electrical signal between non-excitable cells within a resolving infarct might comprise a simple means to decrease post-infarction arrhythmia risk. We therefore tested lentivirus-mediated delivery of the gap-junction protein Connexin 43 (Cx43) into acute myocardial lesions. Cx43 was expressed in (myo)fibroblasts and CD45 cells within the scar and provided prominent and long lasting arrhythmia protection in vivo. Optical mapping of Cx43 injected hearts revealed enhanced conduction velocity within the scar, indicating Cx43-mediated electrical coupling between myocytes and (myo)fibroblasts. Thus, Cx43 gene therapy, by direct in vivo transduction of non-cardiomyocytes, comprises a simple and clinically applicable biological therapy that markedly reduces post-infarction VT.

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References

Berul C, Aronovitz M, Wang P, Mendelsohn M . In vivo cardiac electrophysiology studies in the mouse. Circulation. 1996; 94(10):2641-8. DOI: 10.1161/01.cir.94.10.2641. View

Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M . Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem. 2002; 383(5):725-37. DOI: 10.1515/BC.2002.076. View

Hofmann A, Wenzel D, Becher U, Freitag D, Klein A, Eberbeck D . Combined targeting of lentiviral vectors and positioning of transduced cells by magnetic nanoparticles. Proc Natl Acad Sci U S A. 2009; 106(1):44-9. PMC: 2629186. DOI: 10.1073/pnas.0803746106. View

Stockigt F, Brixius K, Lickfett L, Andrie R, Linhart M, Nickenig G . Total beta-adrenoceptor knockout slows conduction and reduces inducible arrhythmias in the mouse heart. PLoS One. 2012; 7(11):e49203. PMC: 3486811. DOI: 10.1371/journal.pone.0049203. View

Danik S, Rosner G, Lader J, Gutstein D, Fishman G, Morley G . Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. FASEB J. 2007; 22(4):1204-12. PMC: 2726820. DOI: 10.1096/fj.07-8974com. View

Quinn T, Camelliti P, Rog-Zielinska E, Siedlecka U, Poggioli T, OToole E . Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics. Proc Natl Acad Sci U S A. 2016; 113(51):14852-14857. PMC: 5187735. DOI: 10.1073/pnas.1611184114. View

Roell W, Lu Z, Bloch W, Siedner S, Tiemann K, Xia Y . Cellular cardiomyoplasty improves survival after myocardial injury. Circulation. 2002; 105(20):2435-41. DOI: 10.1161/01.cir.0000016063.66513.bb. View

Li G, Sun H, Chen J, Zhou Y, Tse H, Lau C . Characterization of multiple ion channels in cultured human cardiac fibroblasts. PLoS One. 2009; 4(10):e7307. PMC: 2751830. DOI: 10.1371/journal.pone.0007307. View

Menasche P, Alfieri O, Janssens S, Mckenna W, Reichenspurner H, Trinquart L . The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008; 117(9):1189-200. DOI: 10.1161/CIRCULATIONAHA.107.734103. View

10.

Moss A, Zareba W, Hall W, Klein H, Wilber D, Cannom D . Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346(12):877-83. DOI: 10.1056/NEJMoa013474. View

11.

Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren J . Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med. 2006; 203(10):2315-27. PMC: 2118112. DOI: 10.1084/jem.20061469. View

12.

Sadahiro T, Yamanaka S, Ieda M . Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications. Circ Res. 2015; 116(8):1378-91. DOI: 10.1161/CIRCRESAHA.116.305374. View

13.

Nam Y, Song K, Olson E . Heart repair by cardiac reprogramming. Nat Med. 2013; 19(4):413-5. PMC: 3790637. DOI: 10.1038/nm.3147. View

14.

Zufferey R, Donello J, Trono D, Hope T . Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol. 1999; 73(4):2886-92. PMC: 104046. DOI: 10.1128/JVI.73.4.2886-2892.1999. View

15.

van Laake L, Passier R, den Ouden K, Schreurs C, Monshouwer-Kloots J, Ward-van Oostwaard D . Improvement of mouse cardiac function by hESC-derived cardiomyocytes correlates with vascularity but not graft size. Stem Cell Res. 2009; 3(2-3):106-12. DOI: 10.1016/j.scr.2009.05.004. View

16.

Chen W, Frangogiannis N . Fibroblasts in post-infarction inflammation and cardiac repair. Biochim Biophys Acta. 2012; 1833(4):945-53. PMC: 3541439. DOI: 10.1016/j.bbamcr.2012.08.023. View

17.

Kreuzberg M, Schrickel J, Ghanem A, Kim J, Degen J, Janssen-Bienhold U . Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node. Proc Natl Acad Sci U S A. 2006; 103(15):5959-64. PMC: 1458680. DOI: 10.1073/pnas.0508512103. View

18.

Paulis L, Klein A, Ghanem A, Geelen T, Coolen B, Breitbach M . Embryonic cardiomyocyte, but not autologous stem cell transplantation, restricts infarct expansion, enhances ventricular function, and improves long-term survival. PLoS One. 2013; 8(4):e61510. PMC: 3621863. DOI: 10.1371/journal.pone.0061510. View

19.

Rog-Zielinska E, Norris R, Kohl P, Markwald R . The Living Scar--Cardiac Fibroblasts and the Injured Heart. Trends Mol Med. 2016; 22(2):99-114. PMC: 4737999. DOI: 10.1016/j.molmed.2015.12.006. View

20.

Olsson S . Pathophysiology of re-entrant dysrhythmias. Eur Heart J. 1984; 5 Suppl B:19-23. DOI: 10.1093/eurheartj/5.suppl_b.19. View