Harding P, Yang XP, Yang J, Shesely E, He Q, LaPointe MC. Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice. Am J Physiol Heart Circ Physiol 298: H623-H632, 2010. First published December 11, 2009; doi:10.1152/ajpheart.00746.2009.-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 THE PREVALENCE OF DILATED CARDIOMYOPATHY (DCM) is increasing every year and currently accounts for ϳ25% of cases of congestive heart failure. Its occurrence is greater in males and African Americans than in females or Caucasians. DCM is characterized by left ventricular dilatation and systolic dysfunction (i.e., impaired ejection fraction, EF). Ventricular wall thickness can be less than or equal to that of a normal heart, and fibrosis is present to a variable degree. The three major causes of DCM are inflammation, toxic stress (e.g., alcoholism), and genetics (autosomal dominant inheritance). For genetic forms of the disease, the penetrance is variable and age dependent (5).Animal models of DCM have been created by either selectively knocking out (KO) or over expressing a gene (1,3,6,10,16,22,32,36, 43). In most cases, the genes were chosen in a targeted approach because of studies showing functional significance of the gene product in vitro in myo...

The findings of this study showed that considerable amounts of myocardial constructive protein degradation and release due to destruction of cardiac myocytes occurred early after severe burns. The inflammatory mediators released after burn injury may be involved in the pathogenesis of myocardial destruction.