Temporary, Systemic Inhibition of the WNT/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct.
Temporary, Systemic Inhibition of the WNT/β-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct.
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DOI：
10.16966/2472-6990.111
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Young PP
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文献类型：
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作者：
Bastakoty D;Saraswati S;Joshi P;Atkinson J;Feoktistov I;Liu J;Harris JL;Young PP
心肌梗死（MI）后，WNT/β-catenin通路在心脏中被暂时激活。尽管来自遗传模型的数据表明WNT通路的积极和消极作用取决于所使用的模型，但治疗性抑制WNT通路对损伤后结局和所涉及的细胞介质的影响尚不完全清楚。使用一种新获得的小分子GNF-6231，通过阻断所有WNT配体的分泌来避免WNT通路的激活，我们试图研究在梗死后暂时抑制WNT通路是否可以减轻损伤后心功能障碍和纤维化，以及产生这种作用的细胞机制。心肌梗死后静脉注射GNF-6231对C57Bl/6小鼠的WNT通路进行药理学抑制，可显著降低心功能下降（第30天，GNF-6231治疗组为38.71±4.13%，对照组为34.89±4.86%），防止不良心脏重构，减少梗死面积（9.07±3.98%，对照组为17.18±4.97%）。WNT抑制增强了间质细胞的增殖，特别是在远端心肌，抑制了心肌细胞的凋亡，并减少了梗死周围区域肌成纤维细胞的增殖。体外研究表明，抑制WNT可增加Sca1+心肌祖细胞的增殖，提高心肌细胞的存活率，抑制心肌成纤维细胞合成I型胶原。在心肌梗死后立即使用口服生物有效药物对WNT通路进行全身、暂时的药理学抑制，可改善小鼠的功能、减少不良重构和减少梗死面积。治疗性抑制WNT影响梗死修复的多个方面：促进心脏祖细胞和其他间质细胞的增殖，抑制肌成纤维细胞增殖，提高心肌细胞存活率，降低肌成纤维细胞的I型胶原基因表达。我们的数据表明，WNT抑制疗法作为一类新的药物，在推动心肌梗死后修复和预防心力衰竭方面具有很好的作用。
The WNT/β-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles for the WNT pathway depending on the model used, the effect of therapeutic inhibition of WNT pathway on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231, which averts WNT pathway activation by blocking secretion of all WNT ligands, we sought to investigate whether therapeutic inhibition of the WNT pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for the effects. Pharmacologic inhibition of the WNT pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in vehicle-treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). WNT inhibition augmented proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast proliferation in the peri-infarct region. In vitro studies showed that WNT inhibition increased proliferation of Sca1+ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts. Systemic, temporary pharmacologic inhibition of the WNT pathway using an orally bioavailable drug immediately following MI resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic WNT inhibition affected multiple aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation, improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for WNT inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.