title: Loss of cardiomyocyte integrin-linked kinase produces an arrhythmogenic cardiomyopathy in mice.
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.
  
  
  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.affiliation: 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.).
authors.forename: Khai Le
authors.initials: KL
authors.lastname: Quang
authors.affiliation: 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.).
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.affiliation: 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.).
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.affiliation: 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.).
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: 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.).
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.affiliation: 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.).
authors.forename: Artavazd
authors.initials: A
authors.lastname: Tadevosyan
authors.affiliation: 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.).
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Shi
authors.affiliation: 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.).
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.affiliation: 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.).
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: 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.).
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: 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.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D009202:Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D004247:DNA; D004195:Disease Models, Animal; D004562:Electrocardiography; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000099200:Scaffold Protein ILK
chemical_list: D004247:DNA; D024642:Potassium Channels, Voltage-Gated; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
keywords: cardiomyopathies; integrin-linked kinase; potassium channels; sudden cardiac death; ventricular tachycardia