Khai Le Quang1, Ange Maguy1, Xiao-Yan Qi1, Patrice Naud1, Feng Xiong1, Artavazd Tadevosyan1, Yan-Fen Shi1, Denis Chartier1, Jean-Claude Tardif1, Dobromir Dobrev1, Stanley Nattel2. 1. From the Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., A.M., X.-Y.Q., P.N., F.X., A.T., Y.-F.S., D.C., C.T., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (F.X., S.N.); and Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.). 2. From the Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., A.M., X.-Y.Q., P.N., F.X., A.T., Y.-F.S., D.C., C.T., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (F.X., S.N.); and Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.). stanley.nattel@icm-mhi.org.
Abstract
BACKGROUND: Integrin-linked kinase (ILK), a serine/threonine protein kinase, has roles in cell signaling and molecular scaffolding. ILK mutation/deletion causes cardiomyopathic phenotypes, but the functional and electrophysiological features have not been characterized. This study investigated the structural, functional, ion channel, and electrophysiological changes associated with cardiomyocyte-directed ILK deletion in mice. METHODS AND RESULTS: Adult mice with cardiomyocyte-directed ILK knockout were compared with littermate controls. Knockout mice showed markedly increased mortality, with sudden death beginning after 5 weeks and 100% mortality at 18 weeks. In 10-week-old knockout mice, spontaneous and inducible ventricular tachyarrhythmias were common, occurring in 60% and 86%, respectively, and absent in controls (P<0.001, P<0.05 versus knockout mice). Ventricular refractoriness was prolonged, along with both QRS and QT interval. Action potentials were prolonged and displayed triggered activity. A wide range of ion currents were downregulated, including total, fast and slow components of transient outward K(+) current and inward rectifier K(+) current, along with corresponding ion channel subunit genes, providing a plausible explanation of action potential prolongation. At 5 weeks, only voltage-dependent K(+) currents were reduced, possibly related to direct ILK-Kv4.2 subunit interactions. Action potentials were prolonged, but no arrhythmias or cardiac dysfunction were noted. Structural remodeling was prominent at 10 weeks: connexin-43 was downregulated and redistributed to lateral cell margins, and left ventricular fibrosis occurred, with a strong regional distribution (predominating in the basal left ventricle). Conduction was slowed. High-throughput quantitative polymerase reaction gene-expression studies in 10-week-old ILK knockout showed upregulation of structural, remodeling and fibrosis-related genes, and downregulation of a wide range of ion channel and transporter subunits. CONCLUSIONS: Cardiomyocyte ILK deletion produces a lethal arrhythmogenic cardiomyopathy associated with important ion channel and structural remodeling.
BACKGROUND:Integrin-linked kinase (ILK), a serine/threonine protein kinase, has roles in cell signaling and molecular scaffolding. ILK mutation/deletion causes cardiomyopathic phenotypes, but the functional and electrophysiological features have not been characterized. This study investigated the structural, functional, ion channel, and electrophysiological changes associated with cardiomyocyte-directed ILK deletion in mice. METHODS AND RESULTS: Adult mice with cardiomyocyte-directed ILK knockout were compared with littermate controls. Knockout mice showed markedly increased mortality, with sudden death beginning after 5 weeks and 100% mortality at 18 weeks. In 10-week-old knockout mice, spontaneous and inducible ventricular tachyarrhythmias were common, occurring in 60% and 86%, respectively, and absent in controls (P<0.001, P<0.05 versus knockout mice). Ventricular refractoriness was prolonged, along with both QRS and QT interval. Action potentials were prolonged and displayed triggered activity. A wide range of ion currents were downregulated, including total, fast and slow components of transient outward K(+) current and inward rectifier K(+) current, along with corresponding ion channel subunit genes, providing a plausible explanation of action potential prolongation. At 5 weeks, only voltage-dependent K(+) currents were reduced, possibly related to direct ILK-Kv4.2 subunit interactions. Action potentials were prolonged, but no arrhythmias or cardiac dysfunction were noted. Structural remodeling was prominent at 10 weeks: connexin-43 was downregulated and redistributed to lateral cell margins, and left ventricular fibrosis occurred, with a strong regional distribution (predominating in the basal left ventricle). Conduction was slowed. High-throughput quantitative polymerase reaction gene-expression studies in 10-week-old ILK knockout showed upregulation of structural, remodeling and fibrosis-related genes, and downregulation of a wide range of ion channel and transporter subunits. CONCLUSIONS: Cardiomyocyte ILK deletion produces a lethal arrhythmogenic cardiomyopathy associated with important ion channel and structural remodeling.
Authors: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Andreas Brodehl; Darrell D Belke; Lauren Garnett; Kristina Martens; Nelly Abdelfatah; Marcela Rodriguez; Catherine Diao; Yong-Xiang Chen; Paul M K Gordon; Anders Nygren; Brenda Gerull Journal: PLoS One Date: 2017-03-24 Impact factor: 3.240