Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional effects of CTGF inhibition in a transgenic mouse model of dilated cardiomyopathy

ABSTRACT: Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. To test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase CÎµ (PKCÎµ) mouse model of DCM. Transgenic mice expressing constitutively active PKCÎµ in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to heart failure, cardiac fibrosis, and increased mortality. Beginning at 3 months of age, mice were treated with an antibody to CTGF (FG-3149) or non-immune IgG control antibody for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCÎµ mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCÎµ mice, but significantly decreased by CTGF inhibition, however total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCÎµ mice suggests that CTGF inhibition may benefit patients with DCM. Total RNA was isolated from the left ventricle of 6-month-old PKCÎµ transgenic mice or nontransgenic FVB/N controls 3 months after initiation of treatment with IgG (n=10 biological replicates each) or anti-CTGF antibody FG-3149 (n=12 each) and hybridized to Affymetrix 430A 2.0 microarrays. CEL files were processed by GCRMA and rescaled using median per-gene normalization in GeneSpring GX 7.3.1.

ORGANISM(S): Mus musculus

SUBMITTER: Mark Sternlicht

PROVIDER: E-GEOD-68857 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy.

Koshman Yevgeniya E YE Sternlicht Mark D MD Kim Taehoon T O'Hara Christopher P CP Koczor Christopher A CA Lewis William W Seeley Todd W TW Lipson Kenneth E KE Samarel Allen M AM

Journal of molecular and cellular cardiology 20151105 Pt B

Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective tissue growth factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes dev ...[more]

PMID: 26549358

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Project description:Background: Galectin-3 is upregulated in heart disease, and its inhibition has been reported to confer benefits on cardiac remodeling and dysfunction. It remains unknown whether galectin-3 plays a biological role in a setting of dilated cardiomyopathy (DCM). We determined galectin-3 expression in transgenic (TG) mice with cardiac-restricted overexpression of mammalian sterile 20-like kinase 1 (Mst1-TG), and studied the effects of pharmacological and genetic inhibition of galectin-3 on the DCM phenotype. Methods and results: The DCM phenotype of male Mst1-TG mice was assessed at 2, 3 and 6 months of age. Galectin-3 deletion in Mst1-TG mice was achieved by cross-breeding Mst1-TG with galectin-3 knockout (KO) mice to produce genotypes of non-TG (nTG), KO, Mst1-TG, and Mst1-TG mice with partial or complete deletion of the galectin-3 gene. Pharmacological inhibition of galectin-3 was tested by treating Mst1-TG mice with modified citrus pectin for 4 months. Changes in the DCM phenotype were assessed by serial echocardiography, ECG recording and biochemical assays. Mst1-TG mice exhibited upregulated levels of cardiac galectin-3 expression by 40~50-fold, atrial dilatation, reduced left ventricular (LV) ejection fraction, increased LV volume at systole and diastole, atrial conduction delay, severe cardiac fibrosis, and upregulated fibrosis-related genes. Galectin-3 gene deletion in Mst1-TG mice attenuates increased LV volume at systole and diastole, atrial conduction delay and cardiac fibrogenesis. Treatment with modified citrus pectin in Mst1-TG mice did not confer benefit on the DCM phenotype, possibly due to the very high expression of galectin-3. Conclusion: Galectin-3 expression is markedly increased in Mst1-TG hearts exhibiting DCM. Galectin-3 gene deletion effectively suppressed cardiac fibrotic signaling and LV dilatation, and was associated with better function. Thus, suppression of galectin-3 expression may represent a potential therapeutic approach in DCM. The development of new galectin-3 inhibitors are warranted.

Dataset Information

Transcriptional effects of CTGF inhibition in a transgenic mouse model of dilated cardiomyopathy

Publications

Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy.

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