Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA 19140, USA.
Department of Biomedical Engineering, University of Alabama at Birmingham, 1675 University Blvd., Volker Hall G094, Birmingham, AL 35294, USA.
Cardiovasc Res. 2017 Jul 1;113(8):938-949. doi: 10.1093/cvr/cvx052.
Increased miR-375 levels has been implicated in rodent models of myocardial infarction (MI) and with patients with heart failure. However, no prior study had established a therapeutic role of miR-375 in ischemic myocardium. Therefore, we assessed whether inhibition of MI-induced miR-375 by LNA anti-miR-375 can improve recovery after acute MI.
Ten weeks old mice were treated with either control or LNA anti miR-375 after induction of MI by LAD ligation. The inflammatory response, cardiomyocyte apoptosis, capillary density and left ventricular (LV) functional, and structural remodelling changes were evaluated. Anti-miR-375 therapy significantly decreased inflammatory response and reduced cardiomyocyte apoptosis in the ischemic myocardium and significantly improved LV function and neovascularization and reduced infarct size. Repression of miR-375 led to the activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and increased AKT phosphorylation on Thr-308 in experimental hearts. In corroboration with our in vivo findings, our in vitro studies demonstrated that knockdown of miR-375 in macrophages modulated their phenotype, enhanced PDK-1 levels, and reduced pro-inflammatory cytokines expression following LPS challenge. Further, miR-375 levels were elevated in failing human heart tissue.
Taken together, our studies demonstrate that anti-miR-375 therapy reduced inflammatory response, decreased cardiomyocyte death, improved LV function, and enhanced angiogenesis by targeting multiple cell types mediated at least in part through PDK-1/AKT signalling mechanisms.
miR-375 水平的升高已被牵涉到心肌梗死（MI）的啮齿动物模型和心力衰竭患者中。然而，之前没有研究确立过 miR-375 在缺血性心肌中的治疗作用。因此，我们评估了通过 LNA 抗 miR-375 抑制 MI 诱导的 miR-375 是否可以改善急性 MI 后的恢复。
在通过 LAD 结扎诱导 MI 后，10 周龄的小鼠接受对照或 LNA 抗 miR-375 治疗。评估了炎症反应、心肌细胞凋亡、毛细血管密度和左心室（LV）功能以及结构重塑的变化。抗 miR-375 治疗显著降低了缺血心肌中的炎症反应和心肌细胞凋亡，并显著改善了 LV 功能和新生血管形成，减少了梗死面积。miR-375 的抑制导致 3-磷酸肌醇依赖性蛋白激酶 1（PDK-1）的激活，并增加了实验心脏中 AKT 在 Thr-308 上的磷酸化。与我们的体内发现相吻合，我们的体外研究表明，在巨噬细胞中敲低 miR-375 可调节其表型，增强 PDK-1 水平，并在 LPS 挑战后减少促炎细胞因子的表达。此外，miR-375 水平在衰竭的人心组织中升高。
总之，我们的研究表明，抗 miR-375 治疗通过靶向多种细胞类型，减少炎症反应，减少心肌细胞死亡，改善 LV 功能，并增强血管生成，至少部分通过 PDK-1/AKT 信号机制介导。
