小鼠心肌梗死后经S100A4-shRNA治疗后左心室局部和整体收缩功能的改善。
Improvements in left ventricular regional and global systolic function following treatment with S100A4-shRNA after myocardial infarction in mice.
作者信息
Qian Lijun, Zhang Yanjuan, Zhu Menglin, Xie Feng, Porter Thomas R, Xu Di
机构信息
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
出版信息
Quant Imaging Med Surg. 2019 Jun;9(6):1066-1075. doi: 10.21037/qims.2019.05.25.
BACKGROUND
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.
METHODS
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.
RESULTS
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% 20.25%±1.02%, pRSt: 76.75±3.18 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.
CONCLUSIONS
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.
背景
S100A4在心肌梗死（MI）后的心脏纤维化中起重要作用，但其对心肌力学和重塑的影响尚不清楚。我们假设，使用短发夹（sh）RNA抑制S100A4可改善斑点追踪超声心动图（STE）测定的局部和整体左心室（LV）收缩功能。本研究旨在探讨STE能否描绘S100A4-shRNA在MI中的疗效和安全性。
方法
总共48只小鼠被随机分配到假手术+S100A4-shRNA、假手术+乱序（Scr）序列-shRNA、MI+S100A4-shRNA和MI+Scr-shRNA组（每组n = 12），在通过左前降支结扎产生MI后进行心肌内注射靶向药物。在基线以及MI后第7、14和28天，使用GE Vivid 7超声（il3L线性探头，10.0 - 14.0 MHz）和Echopac PC软件进行二维STE和M型超声心动图检查。从短轴中部图像的6个节段分析径向应变，每个心动周期采集20 - 30帧。进行死后蛋白质免疫印迹、免疫组织化学和Masson三色染色以量化梗死面积并检测S100A4的抑制情况。
结果
STE检测到MI + S100A4-shRNA组在MI后第14天峰值径向应变（pRS）和达到峰值径向应变的时间（pRSt）有统计学意义的改善（P < 0.05），特别是在LV前间隔壁（pRS：23.83%±1.12%对20.25%±1.02%，pRSt：76.75±3.18对92.00±3.69毫秒，P < 0.05）。给予S100A4-shRNA 1个月后，根据小鼠的STE和M型追踪结果，MI + S100A4-shRNA组的心脏功能得到改善。此外，生化和组织病理学检查均发现MI + S100A4-shRNA组的心脏纤维化减轻。
结论
S100A4-shRNA可作为治疗靶点，以改善MI后的局部变形并减轻心脏纤维化。二维STE有助于对小鼠LV收缩功能进行早期和全面评估。
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