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

Abstract

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. FASEB J. 27, 4254–4265 (2013). www.fasebj.org