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Effect of Serum Response Factor (SRF) gene deletion on the adult cardiac gene expression at baseline and in response to phenylephrine

ABSTRACT: The objective of this study is to assess the effects of the Serum Response Factor deletion on the cardiac gene expression program at different time points after the deletion (day 8 and day 25) and to compare the response of SRF-deficient heart and control heart to phenylephrine, an alpha-adrenergic agonist triggering cardiac hypertrophy. To generate cardiomyocyte-specific SRF knockout, 10 week-old mice homozygous for the [SRF-flex2neo] allele bearing one copy of the [alphaMHC-MerCreMer] transgene (SRFHKO mice) (Reference 1) were injected i.p. with 0.7mg of tamoxifen for 3 days. All control (SRF-flex2neo littermates) and SRFHKO mice were systematically injected with tamoxifen to normalize for any effects due to tamoxifen. For the mice treated with phenylephrine (PE), the drug was administrated at 80 mg/kg/day from day 10 to day 25 after the first day of tamoxifen injection, using Alzet osmotic minipumps. Reference: Temporally controlled onset of dilated cardiomyopathy through disruption of the SRF gene in adult heart. Parlakian A, Charvet C, Escoubet B, Mericskay M, Molkentin JD, Gary-Bobo G, De Windt LJ, Ludosky MA, Paulin D, Daegelen D, Tuil D, Li Z. Circulation. 2005 Nov 8;112(19):2930-9. PMID: 16260633

ORGANISM(S): Mus musculus

PROVIDER: GSE84142 | GEO | 2017/12/21

SECONDARY ACCESSION(S): PRJNA328137

REPOSITORIES: GEO

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Project description:Rationale: MicroRNAs play key roles in hypertrophic stress responses. miR-378(-3p) is a highly abundant, cardiomyocyte-enriched microRNA whose downregulation in pressure-overload has been suggested as detrimental to the heart. Previous studies have utilized systemic anti-miR or microRNA-encoding virus administration, and thus questions regarding the cardiomyocyte-autonomous roles of miR-378 remain. Objective: To examine whether persistent overexpression of miR-378 in cardiomyocytes alters the phenotype of the unstressed heart, whether its overexpression is beneficial or deleterious in the setting of pressure-overload, and to comprehensively identify its cardiomyocyte-specific effects on mRNA regulation. Methods and Results: Cardiac function was compared in young (10-12 week-old) mice overexpressing miR-378 in the heart under the control of the Myh6 promoter (alphaMHC-miR-378 mice), in older (40 week-old) mice and their age-matched wild-type controls. Older alphaMHC-miR-378 mice exhibited decreased fractional shortening and modest chamber dilation with an increase in cardiomyocyte length. When subjected to pressure-overload, cardiomyocyte length was increased in young alphaMHC-miR-378 mice, but fractional shortening declined precipitously over two weeks. Transcriptome profiling of wild-type and alphaMHC-miR-378 hearts in unstressed and pressure-overload conditions revealed dysregulation of several upstream metabolic and mitochondrial genes in alphaMHC-miR-378 hearts, compromising the reprogramming that occurs during early adaptation to pressure overload. Ago2 immunoprecipitation with mRNA sequencing revealed novel miR-378 cardiac mRNA targets including Akt1 and Epac2 and demonstrated the contextual nature of previously described miR-378 targeting events. Conclusions: Long-term upregulation of miR-378 levels in the heart is not innocuous and exacerbates contractile dysfunction in pressure-overload hypertrophy through numerous signaling mechanisms.

Project description:To identify in vivo new cardiac SRF target genes and to study the response of these novel genes to SRF overexpression, we employed a cardiac-specific, transgenic mouse model that has a phenotype in young adulthood which resembles that of the typically aged heart. Using this “cardiac aging” model, we identified 207 genes that are important to cardiac function that were differentially expressed in vivo. Among them, 192 genes had SRF binding motifs (56 with CArG and 136 with CArG-like elements) in their promoter region. Fifty-one of 56 genes with classic CArG elements were not previously reported. These SRF target genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes were significantly increased. Using public databases of mouse models of stress, we also found that altered expression of the SRF target genes occurred in these hearts as well. Thus, SRF target genes are actively regulated under various physiological and pathological conditions, including hemodynamic stress. The mild elevation of SRF protein in the rodent heart that is observed during typical adult aging may have a major impact on many SRF target genes, thereby affecting cardiac structure and performance. In addition, these results could help to enhance our understanding of SRF regulation of cellular processes, including metabolic and cytoskeletal function. The generation and characterization of transgenic mice with mild cardiac-specific overexpression of SRF was previously reported (Zhang et al., 2003). At 6 months of age, the transgenic mice manifested cardiac changes suggestive of an “aged heart” (Zhang et al., 2003). Therefore, 6-month-old transgenic and non-transgenic mice were used in this study. Cardiac gene expression in SRF Tg heart was compared to that of wild-type mice.

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Effect of Serum Response Factor (SRF) gene deletion on the adult cardiac gene expression at baseline and in response to phenylephrine

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