Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction

Ding, Liang; Li, Dong; Chen, Xin; Zhang, Lujie; Xu, Xiaoyu; Ferro, Albert; Xu, Biao

doi:10.1161/circulationaha.109.870725

Cited by 75 publications

(76 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39,40 Therapeutic strategies designed to specifically attenuate postinfarction remodeling would represent a promising new approach to improve the symptoms and prognosis of patients with HF. The majority of basic and clinical studies of cardiac regeneration have recently focused on cell-based therapies.…”

Section: Discussionmentioning

confidence: 99%

GATA-4 Is an Angiogenic Survival Factor of the Infarcted Heart

Rysä

Tenhunen²,

Serpi³

et al. 2010

Circ: Heart Failure

View full text Add to dashboard Cite

Background-Recent data suggest that GATA-4 is an antiapoptotic factor required for adaptive responses and a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of postinfarction left ventricular remodeling represents an important target for therapeutic interventions. Here, we studied the role of GATA-4 as a mediator of postinfarction remodeling in rats. Methods and Results-Myocardial infarction, caused by ligating the left anterior descending coronary artery, significantly decreased the DNA binding activity of GATA-4 at day 1, whereas at 2 weeks the GATA-4 DNA binding was significantly upregulated. To determine the functional role of GATA-4, peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4 was done before left anterior descending coronary artery ligation. Hearts treated with GATA-4 gene transfer exhibited significantly increased ejection fraction and fractional shortening. Accordingly, infarct size was significantly reduced. To determine the cardioprotective mechanisms of GATA-4, myocardial angiogenesis, rate of apoptosis, c-kitϩ cardiac stemlike cells, and genes regulated by GATA-4 were studied. The number of capillaries and stemlike cells was significantly increased, and decreased apoptosis was observed. Conclusion-These results indicate that the reversal of reduced GATA-4 activity prevents adverse postinfarction remodeling through myocardial angiogenesis, antiapoptosis, and stem cell recruitment. GATA-4 -based gene transfer may represent a novel, efficient therapeutic approach for heart failure. (Circ Heart Fail. 2010;3:440-450.)Key Words: myocardial infarction Ⅲ heart failure Ⅲ angiogenesis Ⅲ gene therapy A dverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause of heart failure (HF) and death. [1][2][3] The molecular mechanisms of post-MI remodeling process are not fully understood but involve alterations in specific signaling molecules, transcription factors (TFs), and their respective downstream pathways. 3 GATA-4 is a zincfinger TF that functions as a key regulator of numerous cardiac genes, such as atrial natriuretic peptide, B-type natriuretic peptide, ␣-myosin heavy chain, and ␤-myosin heavy chain. 4 GATA-4 is also critical for cardiac development, as homozygous GATA-4 -deficient embryos die within 7 to 10 days post coitum owing to defects in ventral morphogenesis and heart tube formation. 5,6 Studies of alleles that cause partial loss of GATA-4 function and conditional deletion of GATA-4 have demonstrated it necessary also for the later phases of heart development and morphogenesis. [7][8][9] Mutations in the human GATA-4 gene have been identified as genetic causes of congenital heart disease. 10,11 In the adult heart, GATA-4 seems to have a unique dual role, on the 1 hand as a mediator of the hypertrophic response and as a survival factor on the other. GATA-4 is required for cardiomyocyte response to hypertrophic stimuli 12 and has been suggested as a nuclea...

show abstract

Section: Discussionmentioning

confidence: 99%

GATA-4 Is an Angiogenic Survival Factor of the Infarcted Heart

Rysä

Tenhunen²,

Serpi³

et al. 2010

Circ: Heart Failure

View full text Add to dashboard Cite

show abstract

“…4C). One manganese ion appeared unambiguously as a relatively high peak (10) in the 1F o -F c electron density map. The position of the manganese ion in the Mn-bound form is almost identical to that of the magnesium ion in the Mg-bound form.…”

Section: Structure Of the Ilk Kd/␣-parvin Ch2 Complex Bound To Mnatp mentioning

confidence: 97%

Biochemical, Proteomic, Structural, and Thermodynamic Characterizations of Integrin-linked Kinase (ILK)

Fukuda

Knight

Piszczek

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Integrin-linked kinase (ILK) is one of the few evolutionarily conserved focal adhesion proteins involved in diverse cell adhesion-dependent physiological and pathological responses. Despite more than a decade of studies and extensive literature, the kinase function of ILK is controversial. ILK contains a highly degraded kinase active site but it has been argued that ILK may be an unusual manganese (Mn)-dependent serine-threonine kinase that targets specific substrates such as glycogen synthase kinase-3␤ (GSK-3␤). In this study, we have tackled this issue by a systematic bottom-up biochemical, proteomic, structural, and thermodynamic analysis of ILK. We show that recombinant ILK from either bacteria or mammalian cells exhibits no kinase activity on GSK-3␤ in the presence of either Mn 2؉ or the conventional kinase co-factor Mg 2؉ . A comprehensive and unbiased whole cell-based kinase assay using entire mammalian CG-4 and C2C12 cell lysate did not identify any specific ILK substrates. High resolution crystallographic structure analysis further confirmed that the Mn-bound ILK adopts the same pseudo active site conformation as that of the Mg-bound ILK. More importantly, thermodynamic analysis revealed that the K220M mutation, previously thought to inactivate ILK by disrupting ATP binding, significantly impairs the structural integrity and stability of ILK, which provides a new basis for understanding how this mutation caused renal agenesis, a failure of fetal kidney development. Collectively, our data provide strong evidence that ILK lacks intrinsic kinase function. It is a bona fide pseudokinase that likely evolved from an ancestral catalytic counterpart to act as a distinct scaffold to mediate protein-protein interactions during focal adhesion assembly and many other cellular events.The adhesion of cells to the extracellular matrix (ECM) 3 is primarily mediated by heterodimeric integrin transmembrane receptors. Upon activation, the integrin extracellular domain adheres to the ECM by binding to numerous ligands such as fibronectin and fibrinogen. However, for cells to firmly adhere to the ECM, integrins must connect to the backbone of the cell, the actin cytoskeleton, via its cytoplasmic tails (CTs) (1-2). Such connection is mediated by the supramolecular focal adhesion (FAs) complex. The reassembly/disassembly of FAs can lead to dynamic cell adhesion processes such as cell migration and spreading, which are fundamental for a variety of physiological responses. Over the past decades, major effort has been made to search for proteins involved in FA assembly and regulation. Integrin-linked kinase (ILK) was discovered in 1996 as a binding partner of integrin ␤ CTs (3) and was found to critically regulate FAs (4). Genetic and genomic analyses have established that ILK is one of the few essential and evolutionarily conserved proteins coupling integrins to actin (5-7), and its dysregulation has been linked to major human diseases such as heart failure (8 -10) and cancer (11). ILK has a molecular mass of ϳ51 kDa containi...

show abstract

“…4 ILK gene transfer improves cardiac function in post-MI and doxorubicin-induced cardiomyopathies. 5,6 Thus, ILK is a central protein in cardiac function and adaptive responses to a range of stressors, particularly mechanical.…”

Section: Functional Importance Of Ilkmentioning

confidence: 99%

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

Quang

Maguy

et al. 2015

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

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.

show abstract

Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction

Cited by 75 publications

References 30 publications

GATA-4 Is an Angiogenic Survival Factor of the Infarcted Heart

GATA-4 Is an Angiogenic Survival Factor of the Infarcted Heart

Biochemical, Proteomic, Structural, and Thermodynamic Characterizations of Integrin-linked Kinase (ILK)

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

Contact Info

Product

Resources

About