Key result
Cardiac ILK deletion drives lethal cardiomyopathy, marked by ~47-fold higher osteopontin expression.
This study identifies osteopontin as a major downstream effector of ILK in the heart, suggesting that ILK deletion-induced cardiomyopathy is heavily driven by inflammatory pathways.
Answers are grounded in this paper and cite their sources.
Osteopontin blockade transiently mitigates ILK cardiomyopathy in mice; leaves open therapeutic translation to human dilated cardiomyopathy.
BACKGROUND: Integrin-linked kinase (ILK) is a serine/threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood. METHODS AND RESULTS: To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice using α-myosin heavy chain-driven Cre expression. Cardiac-specific ILK knockout mice spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression to compare comprehensive transcriptional profiles of cardiac-specific ILK knockout and wild-type hearts from 10-day-old mice before the development of cardiac dysfunction. Approximately 2×10(6) cDNA clones from each genotype were sequenced, corresponding to 33 274 independent transcripts. A total of 93 genes were altered, using nominal thresholds of >1.4-fold change and P<0.001. The most highly upregulated gene was osteopontin (47-fold increase; P=9.6×10(-45)), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in cardiac-specific ILK knockout mice. CONCLUSIONS: Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
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Dai et al. (2013) studied Dilated cardiomyopathy / Heart failure. Cardiac-specific ILK deletion vs. Wild-type control mice (α-MHC-Cre-; ILK fl/fl) was evaluated on Osteopontin (OPN) gene expression fold-change in 10-day-old mice before cardiac dysfunction development (47-fold increase, p=9.6×10^-45). Cardiomyocyte-specific ILK deletion led to lethal dilated cardiomyopathy characterized by a 47-fold increase in osteopontin expression, which when blocked with antibodies, transiently mitigated functional decline.
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