Improvements in left ventricular regional and global systolic function following treatment with S100A4-shRNA after myocardial infarction in mice.

Abstract

S100A4 plays a vital role in cardiac fibrosis after myocardial infarction (MI), but its effects on myocardial mechanics and remodeling are unknown. We hypothesized that regional and global left ventricular (LV) systolic function as determined by speckle tracking echocardiography (STE) would be improved with inhibition of S100A4 using short hairpin (sh) RNA. This study aimed to investigate whether STE can delineate the efficacy and safety of S100A4-shRNA in MI. A total of 48 mice were randomly assigned to sham+S100A4-shRNA, sham+scrambled (Scr) sequence-shRNA, MI+S100A4-shRNA, and MI+Scr-shRNA groups (n=12 per group) and underwent intramyocardial injection of target agents after MI was produced by left anterior descending ligation. Two-dimensional STE and M-mode echocardiography were performed at baseline and at day 7, 14, and 28 post-MI by GE Vivid 7 ultrasound (il3L linear probe, 10.0-14.0 MHz) and Echopac PC software. Radial strain was analyzed from 6 segments of the mid short axis images with 20-30 frames per cardiac cycle. Post-mortem western blotting, immunohistochemistry, and Masson's trichrome stain were performed to quantify infarct size and detect suppression of S100A4. STE detected a statistically significant improvement in peak radial strain (pRS) and time to peak radial strain (pRSt) by day 14 post-MI in the MI+S100A4-shRNA group (P<0.05), especially in the LV anteroseptal wall (pRS: 23.83%±1.12% vs. 20.25%±1.02%, pRSt: 76.75±3.18 vs. 92.00±3.69 ms, P<0.05). After 1 month of S100A4-shRNA administration, cardiac function improved in the MI+S100A4-shRNA group according to both STE and M-mode tracing in mice. Additionally, both biochemical and histopathological examinations found reduced cardiac fibrosis in the MI+S100A4-shRNA group. S100A4-shRNA can be utilized as a therapeutic target to improve regional deformation and attenuate cardiac fibrosis following MI. Two-dimensional STE is useful in the early and comprehensive assessment of LV systolic function in mice.