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The objective is to study the genetic regulatory mechanism and key pathways of heart failure (HF) from the trascriptome level.
The rat model of post-infarction heart failure was conducted, the mRNA expression profile in left ventricular myocardial tissue of both the HF group and the control group was detected and analyzed by RNA-sequencing. GO annotation, KEGG pathway analysis and GSEA analysis of DEGs were performed. The real-time quantitative PCR (qPCR) was conducted to validate the accuracy of sequencing data. Additionally, Agpat1, Mtfp1, Pdk4, et al were tested in 8 weeks and 10 weeks after operation both in mRNA level and protein level. Finally, we verified the miRNA-mRNA target interaction between miR-122-5p and Agpat1 by dual-luciferase reporter gene system, and then preliminarily explored the cardiomyocyte apoptosis effect of miR-122a-5p and Agpat1 in vitro.
1. A variety of changes in gene expression pattern between control group and HF group were identified.
2.The DEG analysis showed 427 differential expressed genes with 357 up-regulated genes and 70 down-regulated genes when compared to control group.
3.DEGs were found to be enriched in biological regulation, multicellular organisms and stress reaction in GO analysis, and in extracellular matrix receptor interactions, osteoclast differentiation, gelling spot, toll-like receptors signaling pathways and hematopoietic cell pathways in KEGG analysis. The significantly enriched GESA pathways were mainly involved in signal transduction, immune regulation, substance and energy metabolism, and biological synthesis.
4.The expression levels of Agpat1 and Dusp1 gradually decreased suggesting their protective role in HF; the expression level of Pdk4 gradually increased; the expression of Mtfp1 was significantly up-regulated at 8 weeks after myocardial infarction, however decreased gradually and significantly lower than the control group at 10 weeks after myocardial infarction.
5.The cardiomyocyte apoptosis effect of miR-122a-5p with or without AngII and H2O2 induction was confirmed through loss of function and gain of function in the myocardial apoptosis model.
6.The miRNA-mRNA target interaction between miR-122-5p and Agpat1 was proved by dual-luciferase reporter gene system.
7.The protective role of Agpat1 in cell apoptosis was confirmed by construction of over-expression vector in vitro studies.
1.Significant changes in myocardial tissue expression profile in the rat model of post-infarction heart failure have been shown. Several pathways and related genes were involved in the progression of HF.
2.The dynamic expression patterns of Agpat1, Dusp1, Mtfp1 and Pdk4 in different periods of post-infarction heart failure were confirmed, which suggested that genes might have different roles in different time of HF.
3.Inhibition of miR-122a-5p and the increase of Agpat1 may be the effective means to prevent cardiomyocyte apoptosis and ventricular remodeling.