Transcriptome analysis of valosin-containing protein effect on cardiac hypertrophy and dysfunction
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ABSTRACT:
PROVIDER: PRJNA553751 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11770253_1.fastq.gz | Fastqsanger.gz | |||
| SRR11770253_2.fastq.gz | Fastqsanger.gz | |||
| SRR11770254_1.fastq.gz | Fastqsanger.gz | |||
| SRR11770254_2.fastq.gz | Fastqsanger.gz | |||
| SRR11770255_1.fastq.gz | Fastqsanger.gz |
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Project description:Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. Deubiquitinating enzymes (DUBs) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation.This study set out to investigate the role of a DUB, USP25, in pathological cardiac hypertrophy, reveal its molecular mechanism, and hopefully provide a new therapeutic target for heart failure.We revealed increased protein level of USP25 expression in the cardiomyocytes in response to Ang II stimulation. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and TAC treatment. Mechanistically, LC-MS/MS analysis combined with Co-IP was used to identify SERCA2a, an anti-hypertrophy protein, as an interacting protein of USP25. Also, our data showed that USP25 bound to SERCA2a directly via its USP domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium content in cardiomyocytes. Moreover, restoration of USP25 expression via with AAV9 vectors in USP25-/- mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas SERCA2a myocardial overexpression could offset the effect of USP25.
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Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (α-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of α-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon α-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure. Small RNA profiles of control and hypertrophied cardiomyocyte H9c2 cells were generated by deep sequencing using Illumina HiSeq 2000
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