Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

Abstract

Rajan S, Pena JR, Jegga AG, Aronow BJ, Wolska BM, Wieczorek DF. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45: 764 -773, 2013. First published June 25, 2013 doi:10.1152/physiolgenomics.00023.2013.-Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHCassociated mutation in ␣-tropomyosin: Glu ¡ Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. tropomyosin; phospholamban; cardiomyopathy; mouse model CARDIOVASCULAR DISEASE IS the leading cause of mortality in the Western world, with heart failure representing one of the fastest growing subgroups over the past decade. Systolic and diastolic dysfunction is common in patients suffering from many types of heart disease and cardiac failure. In addition, hypertrophic growth of cardiomyocytes occurs in many forms of heart failure and may contribute to the pathogenesis of the failure state.Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in contractile proteins of the cardiac sarcomere, Z-disc proteins, and Ca 2ϩ -handling proteins (5). ␣-tropomyosin (Tm), a thin filament protein of the sarcomere, has been found to encode 11 mutations that lead to FHC (23). Previous work in our laboratories established a transgenic mouse model expressing mutant FHC Tm180 protein (1,7,16,17). This mouse develops severe concentric cardiac hypertrophy with si...

Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

“…Hearts from wild-type or HCM C57BL/6 mice were excised at 2 months of age and subjected to transcriptome analysis. In the Tpm1 mutation model (GSE42892; Rajan et al, 2013 ), FVB/N mice overexpressed mouse Tpm1 containing a point mutation resulting in E180G (Tpm1-E180G). Hearts from wild-type or HCM FVB/N mice were excised at 4 months of age and subjected to transcriptome analysis.…”

“…In this study, we sought to identify DEGs common to five different mouse models of HCM. The transcriptome datasets were downloaded from a public database ( Barrett et al, 2009 ) and were derived from mouse models of HCM caused by: (i) mutation of myosin heavy chain 6 ( Myh6 ) ( Luczak et al, 2011 ), (ii) mutation of Tpm1 ( Rajan et al, 2013 ), (iii) expressing human PLN on a null background ( Wang et al, 2011 ), (iv) KO of Fxn ( Huang et al, 2013 ), and (v) TAC, a model of pressure overload-induced HCM ( Lai et al, 2014 ). We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 ( Gstk1 ) was the only gene downregulated.…”

Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model

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Microarray profiling of long non-coding RNA (lncRNA) associated with hypertrophic cardiomyopathy

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