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GW24-e2270 MicroRNA-378 Plays Regulatory Roles in Pressure Overload-induced Cardiac remodelling
  1. Yuan Jie1,2,
  2. Ye Yong1,
  3. Zhao Tian2,
  4. Zhang Xiaoyi1,
  5. Ding Zhiwen2,
  6. Weng Linqing1,
  7. Zou Yunzeng1

Abstract

Objectives MicroRNAs, as one of key regulators for post-transcriptional gene control, have shown to be involved in cardiovascular diseases. This study aimed to investigate the roles of miR-378 in regulation of cardiac hypertrophy and cardiac fibrosis stimulated by pressure overload.

Methods To construct cardiac remodelling mice models, pressure overload was imposed on the heart of C57B/L6 mice (8 weeks) by constriction of transverse aortic banding (TAC). Chemically modified oligonucleotides miRNA mimics (miR-378-Agomir) and inhibitors (miR-378-Antagomir) treatment started 24 h after TAC by intravenous injections on two consecutive days. Mice were randomly divided into four groups: 1) the TAC group; 2) the TAC-Agomir group; 3) the TAC- Antagomir group; 4) the Sham operation group. Mice after sham or 2 weeks TAC operation were subjected to hemodynamic and echocardiographic measurement. Tissue and serum miR-378 expressions were detected by TaqMan MicroRNA Assay Kit. ANP, BNP, β-MHC, collagen I and collagen III was measured by Real-time PCR. ERK1/2, p-ERK1/2, MMPs and α-SMA expression were analysed by western blotting. Collagen was assessed by immunohistochemistry.

Results We found that miR-378 has a high expression pattern in the heart. After two-week acute pressure overload, the TAC group exhibit prominent cardiac hypertrophic responses and decreased expression of miR-378(p < 0.05) comparing with the sham group. In vivo overexpression of miR-378 in TAC-Agomir group markerly inhibited cardiac hypertrophy, accompanied with downregulation of fetal gene ANP, BNP and β-MHC compared to that of TAC group. Howerver, inhibition of endogenous miR-378 by an infusion of an antagomir caused sustained cardiac hypertrophy, associated with a reinduction of fetal gene expression to a less extent. The p-ERK level was also downregulated in TAC-Agomir group and upregulated in TAC- Antagomir group. In part of cardiac fibrosis, we found that the over-expression of miR-378 of TAC-Agomir group reduced the expression of col I, col III, MMP2, MMP9 and α-SMA(p < 0.05) compared to that of TAC group, whereas down regulation of endogenous miR-378 with anti-miRs promoted collagens and MMPs expression.

Conclusions These findings reveal orchestrating regulatory roles for miR-378 in pressure-overload induced cardiac remodeling. It suggests that miR-378 not only suppresses cardiac hypertrophy by regulating fetal genes expression and ERK1/2 signaling pathway but also controls fibrosis-related genes expression in the heart.

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