Sp1 Mediates a Therapeutic Role of MiR-7a/b in Angiotensin II-Induced Cardiac Fibrosis via Mechanism Involving the TGF-β and MAPKs Pathways in Cardiac Fibroblasts

• DOI: 10.1371/journal.pone.0125513
• Publication Date: 2015-04-29T20:08:37Z
• Authors: Rui Li; Jie Xiao; Xiaoteng Qing; Junhui Xing; Yanfei Xia; Jia Qi; Xiaojun Liu; Sen Zhang; Xi Sheng; Xinyu Zhang; Xiaoping Ji
• Keywords: MAP Kinase Signaling System; Sp1 Transcription Factor; Science; Collagen Type I; 03 medical and health sciences; Cell Movement; Transforming Growth Factor beta; Animals; Rats, Wistar; Extracellular Signal-Regulated MAP Kinases; 0303 health sciences; Angiotensin II; Myocardium; Q; R; Plicamycin; Fibroblasts; Endomyocardial Fibrosis; Rats; 3. Good health; MicroRNAs; Gene Expression Regulation; Matrix Metalloproteinase 9; Medicine; Matrix Metalloproteinase 2; Research Article

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.