Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization.

Autor: Zhang K; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Cloonan PE; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA., Sundaram S; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Liu F; State Key Laboratory of Nonlinear Mechanics, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China., Das SL; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.; Harvard-MIT Program in Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Ewoldt JK; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Bays JL; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Tomp S; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA., Toepfer CN; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK., Marsiglia JDC; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Gorham J; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Reichart D; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Eyckmans J; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Seidman JG; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Seidman CE; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Chen CS; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Oct 15; Vol. 7 (42), pp. eabh3995. Date of Electronic Publication: 2021 Oct 15.
DOI: 10.1126/sciadv.abh3995
Abstrakt: Progressive loss of cardiac systolic function in arrhythmogenic cardiomyopathy (ACM) has recently gained attention as an important clinical consideration in managing the disease. However, the mechanisms leading to reduction in cardiac contractility are poorly defined. Here, we use CRISPR gene editing to generate human induced pluripotent stem cells (iPSCs) that harbor plakophilin-2 truncating variants ( PKP2 tv), the most prevalent ACM-linked mutations. The PKP2 tv iPSC–derived cardiomyocytes are shown to have aberrant action potentials and reduced systolic function in cardiac microtissues, recapitulating both the electrical and mechanical pathologies reported in ACM. By combining cell micropatterning with traction force microscopy and live imaging, we found that PKP2 tvs impair cardiac tissue contractility by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. These findings highlight the interplay between cell-cell adhesions and sarcomeres required for stabilizing cardiomyocyte structure and function and suggest fundamental pathogenic mechanisms that may be shared among different types of cardiomyopathies.
Databáze: MEDLINE