Uitterdijk André, Hermans Kevin C M, de Wijs-Meijler Daphne P M, Daskalopoulos Evangelos P, Reiss Irwin K, Duncker Dirk J, Matthijs Blankesteijn W, Merkus Daphne
Department of Cardiology, Division of Experimental Cardiology, Thoraxcenter Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
Lab Invest. 2016 Feb;96(2):168-76. doi: 10.1038/labinvest.2015.139. Epub 2015 Dec 14.
Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (-41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.
用UM206调节Wnt/Frizzled信号通路可减少小鼠梗死灶扩大并预防心力衰竭的发生，这一效应伴随着梗死灶中肌成纤维细胞数量的增加，提示Wnt/Frizzled信号通路在心肌梗死后的心脏重塑中起关键作用。本研究在再灌注心肌梗死猪模型中研究了用UM206调节Wnt/Frizzled信号通路的效果。为此，对7只心肌梗死猪持续输注UM206，治疗5周。6只对照猪接受赋形剂治疗。另外8只猪接受假手术。通过清醒猪的超声心动图测定心功能。在基线时通过心脏特异性脂肪酸结合蛋白ELISA估计梗死灶质量，并在随访时使用面积测量法进行评估。在随访时用qPCR和/或组织学方法测量Wnt/Frizzled信号通路的成分、肌成纤维细胞的存在情况和细胞外基质。结果显示，与基线相比，UM206治疗使梗死灶质量显著降低（-41±10%），而在对照心肌梗死组中梗死灶质量保持稳定（+3±17%）。心肌梗死后3至5周，对照心肌梗死组出现左心室逐渐扩张，而UM206治疗组的不良重塑停止。与对照心肌梗死猪相比，UM206治疗猪中卷曲蛋白4（Frizzled-4）和卷曲蛋白共受体低密度脂蛋白受体相关蛋白5（LRP5）的mRNA表达增加。在5周随访时，UM206治疗动物梗死组织中的肌成纤维细胞数量显著低于对照组（1.53±0.43%对3.38±0.61%）。本研究表明，UM206治疗可减轻再灌注心肌梗死猪模型中的不良重塑，表明Wnt/Frizzled信号通路是改善梗死灶愈合和限制心肌梗死后重塑的一个有前景的靶点。
