Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure

White, Donald E.; Coutu, Pierre; Shi, Yanfen; Tardif, Jean‐Claude; Nattel, Stanley; Arnaud, René; Dedhar, Shoukat; Muller, William J.

doi:10.1101/gad.1458906

Cited by 149 publications

(167 citation statements)

References 34 publications

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“…We assessed the effects of cardiac Gab1 deletion on Gab1 downstream signaling in hearts of Gab1-cKO and Gab1-WT control mice after 2 weeks of TAC or sham operation. In agreement with previous studies, [28][29][30] TAC increased ERK1/2 phosphorylation in Gab1-WT mice compared with sham control, but this response was impaired in Gab1-cKO mice (Figures 3a and b). TAC also induced p38MAPK phosphorylation in Gab1-WT mice, and this TAC-induced phosphorylation of p38MAPK was further enhanced in Gab1-cKO mice.…”

Section: Resultssupporting

confidence: 93%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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Section: Resultssupporting

confidence: 93%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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“…6, this kinase coordinates cues from ECM, including distinct signal inputs from integrins and growth factor receptor tyrosine kinases. This signaling was shown to regulate the cellular structural integrity and homeostasis in skeletal and cardiac muscle (31,32). The inactivation of ILK results in the loss of structural integrity in cardiac muscle (32), while it does lead to the development of a mild progressive muscular dystrophy, characterized by extensive fibrosis and irregular fiber size with centralized nuclei in skeletal muscle (31,32).…”

Section: Discussionmentioning

confidence: 99%

Time course of gene expression during mouse skeletal muscle hypertrophy

Chaillou

Lee

England

et al. 2013

Journal of Applied Physiology

109

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“…8 All procedures followed National Institutes of Health guidelines and were approved by the Animal Research Ethics Committee of the Montreal Heart Institute. Studies were performed in 5-and 10-week-old mice, as well as age-matched controls, as indicated.…”

Section: Animal Modelmentioning

confidence: 99%

“…8 Phenotypic characterization has been limited: increased mortality, cardiac hypertrophy, ventricular dilation, and reduced LVEF were described in mice with targeted ILK deletion, 8 whereas reduced integrin-binding capacity and loss of endothelial cells were reported with clinical ILK mutationassociated DCM. 9 This study constitutes the first detailed phenotypic characterization of the cardiomyopathy caused by ILK deletion.…”

Section: Ilk-dysfunction Cardiomyopathymentioning

confidence: 99%

“…7,15 ILK functions include both mechanosensitive properties 2 and action as a kinase. 8 Cardioprotective protein kinase B is an important target of ILK phosphorylation: the cardiomyopathy resulting from loss of ILK phosphorylation in PINCH-inactivated zebrafish is reversed by overexpression of constitutively activated protein kinase B. 16 ILK is upstream to a wide range of protein kinases involved in cell growth and cardiac hypertrophy, including protein kinase B, glycogen synthase kinase-3-β, extracellular signal-related kinase, and mammalian target of rapamycin 2 and ILK deletion causes severe cardiomyocyte apoptosis.…”

Section: Functional Importance Of Ilkmentioning

confidence: 99%

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Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

Quang

Maguy

et al. 2015

Circ: Arrhythmia and Electrophysiology

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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.

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Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure

Cited by 149 publications

References 34 publications

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Time course of gene expression during mouse skeletal muscle hypertrophy

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

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