Journal article
Deep Sequence Analysis of Gene Expression Identifies Osteopontin as a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK Knockout Mice
Circulation. Heart failure, Vol.7(1), pp.184-193
01/2014
DOI: 10.1161/CIRCHEARTFAILURE.113.000649
PMID: 24319095
Abstract
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.
Details
- Title: Subtitle
- Deep Sequence Analysis of Gene Expression Identifies Osteopontin as a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK Knockout Mice
- Creators
- Jing Dai - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)Takashi Matsui - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)E. Dale Abel - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)Shoukat Dedhar - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)Robert E Gerszten - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)Christine E Seidman - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)J.G Seidman - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)Anthony Rosenzweig - From the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA (J.D., A.R.); Harvard Medical School, Boston, MA (J.D., R.E.G., A.R.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (T.M.); Endocrinology Division and Program in Molecular Medicine, University of Utah, Salt Lake City (E.D.A.); British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada (S.D.); Massachusetts General Hospital, Boston (R.E.G.)
- Resource Type
- Journal article
- Publication Details
- Circulation. Heart failure, Vol.7(1), pp.184-193
- DOI
- 10.1161/CIRCHEARTFAILURE.113.000649
- PMID
- 24319095
- ISSN
- 1941-3289
- eISSN
- 1941-3297
- Language
- English
- Date published
- 01/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024528802771
Metrics
13 Record Views