Abstract
Myocardial infarction (MI) may cause heart failure and seriously harm human health. During the genesis of cardiac fibrosis after MI, the proliferation and migration of cardiac fibroblasts contribute to secretion and maintenance of extracellular matrix (ECM) components. Many miRNAs have been highly implicated in the processes of cardiac fibrosis after MI. However, the molecular mechanisms for how miRNAs involve in cardiac fibrosis remain largely unexplored. Based on MI model in miniature pigs, the potential miRNAs involved in MI were identified by using small RNA sequencing. Using human cardiac fibroblasts (HCFs) as a cellular model, EdU, Transwell, and the expression of ECM-related proteins were applied to investigate the cell proliferation, migration and collagen synthesis. In this study, using MI model based on miniature pigs, 84 miRNAs were identified as the differentially expressed miRNAs between MI and control group, and miR-144-3p, one of differentially expressed miRNAs, was identified to be higher expressed in infarct area. The cell proliferation, migration activity, and the mRNA and protein levels of the ECM-related genes were significantly increased by miR-144-3p mimic but significantly decreased by miR-144-3p inhibitor in cardiac fibroblasts. Furthermore, miR-144-3p was observed to repress transcription and translation of PTEN, and interfering with the expression of PTEN up-regulated the mRNAs and proteins levels of α-SMA, Col1A1, and Col3A1, and promoted the proliferation and migration of cardiac fibroblasts, which was in line with that of miR-144-3p mimics, but this observation could be reversed by miR-144-3p inhibitor. Collectively, miR-144-3p promotes cell proliferation, migration, and collagen production by targeting PTEN in cardiac fibroblasts, suggesting that miR-144-3p-mediated-PTEN regulation might be a novel therapeutic target for cardiac fibrosis after MI.
Highlights
The myocardial infarction (MI) caused by coronary artery acute or persistent hypoxia-ischemia is a type of cardiovascular disease (Acharya, 2018), which may cause heart failure and seriously harm human health
To further explore the role of miR-144-3p in cardiac fibrosis, the oligonucleotide mimics or inhibitors of miR-144-3p were constructed and transfected into human cardiac fibroblasts (HCFs) cells (Figure 2B). qRT-polymerase chain reaction (PCR) assays confirmed that miR-144-3p mimic markedly increased the expression of miR-144-3p (Figure 2B), and miR144-3p inhibitor significantly decreased the expression of miR144-3p (Figure 2B)
The potential miRNAs that might involve in the processes of cardiac fibrosis after MI were identified in the miniature pigs. 84 miRNAs were identified as the expressed miRNAs (Figure 1 and Supplementary Table S3)
Summary
The myocardial infarction (MI) caused by coronary artery acute or persistent hypoxia-ischemia is a type of cardiovascular disease (Acharya, 2018), which may cause heart failure and seriously harm human health. Much evidence has suggested that MI accounts for approximate 7.6% of the total deaths in China in 2011 (Wang et al, 2017). During the processes of cardiac fibrosis, MI induces the proliferation of fibroblasts, which account for about 70% of cells in the healthy heart (Zak, 1974; Eghbali et al, 1989), to migrate to the injured myocardial site and differentiate to myofibroblasts to deposit fibrillar collagens such as types I (Col1A1) and III (Col3A1) (Shinde and Frangogiannis, 2014; Chistiakov et al, 2016). The excessive ECM deposition leads to ventricular dilation, infarct expansion, and cardiac remodeling, and causes changes in myocardial structure, function, and phenotype (Zamilpa and Lindsey, 2010). MI is critical danger to humans, the molecular mechanism for cardiac fibrosis and ECM deposition after MI remains unclear
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