Abstract
MicroRNA-7a/b (miR-7a/b) protects cardiac myocytes from apoptosis during ischemia/reperfusion injury; however, its role in angiotensin II (ANG II)-stimulated cardiac fibroblasts (CFs) remains unknown. Therefore, the present study investigated the anti-fibrotic mechanism of miR-7a/b in ANG II-treated CFs. ANG II stimulated the expression of specific protein 1 (Sp1) and collagen I in a dose- and time-dependent manner, and the overexpression of miR-7a/b significantly down-regulated the expression of Sp1 and collagen I stimulated by ANG II (100 nM) for 24 h. miR-7a/b overexpression effectively inhibited MMP-2 expression/activity and MMP-9 expression, as well as CF proliferation and migration. In addition, miR-7a/b also repressed the activation of TGF-β, ERK, JNK and p38 by ANG II. The inhibition of Sp1 binding activity by mithramycin prevented collagen I overproduction; however, miR-7a/b down-regulation reversed this effect. Further studies revealed that Sp1 also mediated miR-7a/b-regulated MMP expression and CF migration, as well as TGF-β and ERK activation. In conclusion, miR-7a/b has an anti-fibrotic role in ANG II-treated CFs that is mediated by Sp1 mechanism involving the TGF-β and MAPKs pathways.
Highlights
Cardiac fibrosis involves the excessive accumulation of extracellular matrix (ECM) in the heart, which leads to cardiac dysfunction, and is closely associated with numerous cardiovascular diseases, including hypertension, myocardial infarction and cardiomyopathy
To determine the potential signal transduction pathway involved in miR-7a/b-mediated fibrosis, we evaluated the transforming growth factor β (TGF-β) and mitogen-activated protein kinases (MAPKs) pathways
We found that angiotensin II (ANG II) stimulated matrix metalloproteinases (MMPs)-2 expression/activation and MMP-9 expression in cardiac fibroblasts (CFs), which were repressed by miR-7a/b mimics and mithramycin, suggesting that both miR-7a/b and mithramycin act as MMP repressors
Summary
Cardiac fibrosis involves the excessive accumulation of extracellular matrix (ECM) in the heart, which leads to cardiac dysfunction, and is closely associated with numerous cardiovascular diseases, including hypertension, myocardial infarction and cardiomyopathy. As the most common cell type in the heart, cardiac fibroblasts (CFs) play a pivotal role in the development of cardiac fibrosis via the excessive synthesis of collagens and the degradation of ECM via the production of matrix metalloproteinases (MMPs). The renin-angiotensin system (RAS), PLOS ONE | DOI:10.1371/journal.pone.0125513. The renin-angiotensin system (RAS), PLOS ONE | DOI:10.1371/journal.pone.0125513 April 29, 2015
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