Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice

1 Hypertension and Vascular Research Division, Department of Internal Medicine, and 2 Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, Michigan Submitted August 10, 2009 ; accepted in final form December 4, 2009 Using a line of mice with cardiac-specific knockout...

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Published in:American journal of physiology. Heart and circulatory physiology 2010-02, Vol.298 (2), p.H623-H632
Main Authors: Harding, Pamela, Yang, Xiao-Ping, Yang, James, Shesely, Ed, He, Quan, LaPointe, Margot C
Format: Article
Language:English
Subjects:
Aging
Aging - genetics
Aging - metabolism
Animals
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Dilated - metabolism
Cardiomyopathy, Dilated - pathology
Cells
Chemokines - metabolism
Collagen - metabolism
Cytokines - metabolism
Disease Models, Animal
Disease Progression
Female
Gene expression
Gene Expression Profiling
Genotype & phenotype
Growth Differentiation Factor 15 - genetics
Growth Differentiation Factor 15 - metabolism
Heart
Macrophages - pathology
Male
Mice
Mice, Knockout
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Oxidation
Phenotype
Proteins
Receptors, Prostaglandin E - genetics
Receptors, Prostaglandin E - metabolism
Receptors, Prostaglandin E, EP4 Subtype
Rodents
Sex Characteristics
Stroke Volume - physiology
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Summary:1 Hypertension and Vascular Research Division, Department of Internal Medicine, and 2 Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, Michigan Submitted August 10, 2009 ; accepted in final form December 4, 2009 Using a line of mice with cardiac-specific knockout (KO) of the EP4 receptor gene, experiments were designed to determine whether a cardiac phenotype developed with age. Cardiac function was assessed by echocardiography in 23- to 33-wk-old male and female KO and littermate controls (WT) mice. After echocardiography, hearts were removed to assess weight, and then some were further processed for histology [myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF), and macrophage infiltration] and some for extraction of total RNA and protein. Older male KO mice had reduced ejection fraction (EF) coupled with left ventricular dilatation. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 39% in KO mice. In contrast to male KO mice, 30- to 32-wk-old female KO mice had only a slight reduction in EF. To understand gene expression differences between male WT and KO mice, we performed whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-to 32-wk-old mice. Data indicated that 156 genes were overexpressed in the KO hearts more than twofold, including genes involved in remodeling, inflammation, and oxidative stress. Overexpressed chemokines/cytokines were further examined in hearts of 10- to 12-wk-old male KO mice, and we found that growth differentiation factor-15 (GDF-15) expression was higher in KO than in WT hearts. In conclusion, EP4 knockdown in cardiac myocytes in aged male KO mice is in part associated with increased fibrosis, reduced EF, and dilated cardiomyopathy. Early overexpression of GDF-15 in hearts of male KO mice may contribute to or be a marker of the disease phenotype. The absence of serious cardiac dysfunction in aged female mice suggests a sexual dimorphism in the phenotype. heart; remodeling; growth differentiation factor-15 Address for reprint requests and other correspondence: M. C. LaPointe, Hypertension and Vascular Research Division, E & R Bldg 7099, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202 (e-mail: mlapoin1{at}hfhs.org ).
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00746.2009