miR-17 targets tissue inhibitor of metalloproteinase 1 and 2 to modulate cardiac matrix remodeling

Article

关键词: RANDOMIZED PHASE-1 TRIAL;    MYOCARDIAL-INFARCTION;    ISCHEMIC CARDIOMYOPATHY;    HEART-FAILURE;    BONE-MARROW;    STEM-CELLS;    MICRORNAS;    MICE;    EXPRESSION;    DEFICIENCY;   

DOI  :  10.1096/fj.13-231688

来源: SCIE

【 摘 要 】

We aimed to investigate the role of miR-17 in cardiac matrix remodeling following myocardial infarction (MI). Using real-time PCR, we quantified endogenous miR-17 in infarcted mouse hearts. Compared with related microRNAs, miR-17 was up-regulated most dramatically: 3.7-fold and 2.4-fold in the infarct region 3 and 7 d post-MI, respectively, and 2.4-fold in the border zone at d 3 compared to sham control (P<0.01). Chimeric luciferase reporter constructs were cloned for miR-17 target validation. miR-17 targeted the 3-UTR of TIMP2 and the protein coding region of TIMP1. The miR-17 mimic decreased TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared with the scrambled control. Inhibition of endogenous miR-17 by in vivo antagomir delivery enhanced TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared to the mismatch group, decreased MMP9 activity (P<0.05), reduced infarct size as early as 7 d post-MI (P<0.05), and improved cardiac function (fractional shortening and fractional area contraction, P<0.05) at d 21 and 28 post-MI. Transgenic mice overexpressing miR-17 in the heart confirmed the deleterious role of miR-17 in matrix modulation. Our study suggests that miR-17 participates in the regulation of cardiac matrix remodeling and provides a novel therapeutic approach using miR-17 inhibitors to prevent remodeling and heart failure after MI.Li, S.-H., Guo, J., Wu, J., Sun, Z., Han, M., Shan, S. W., Deng, Z., Yang, B. B., Weisel, R. D., Li, R.-K. miR-17 targets tissue inhibitor of metalloproteinase 1 and 2 to modulate cardiac matrix remodeling.

【 授权许可】

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