Loss of cardiomyocyte integrin-linked kinase produces an arrhythmogenic cardiomyopathy in mice.
Circ Arrhythm Electrophysiol
; 8(4): 921-32, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-26071395
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Arritmias Cardíacas
/
Regulação da Expressão Gênica
/
Proteínas Serina-Treonina Quinases
/
Miócitos Cardíacos
/
Eletrocardiografia
/
Cardiomiopatias
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Circ Arrhythm Electrophysiol
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article