Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, 50 Universiteitssingel, 6229ER Maastricht/PO Box 616, 6200MD Maastricht, Netherlands.
Circulation. 2011 Oct 11;124(15):1626-35. doi: 10.1161/CIRCULATIONAHA.110.976969. Epub 2011 Sep 19.
The molecular pathways that control the wound healing after myocardial infarction (MI) are not completely elucidated. One of these pathways is the Wnt/Frizzled pathway. In this study, we evaluated Frizzled as a novel therapeutic target for MI. These Frizzled proteins act as receptors for Wnt proteins and were previously shown to be expressed in the healing infarct.
Wnt/Frizzled signaling has been studied for decades, but synthetic ligands that interfere with the interaction between Wnts and Frizzled have not been described to date. Here we report the selection of 3 peptides derived from regions of high homology between Wnt3a and Wnt5a that act as antagonists for Frizzled proteins. UM206, the peptide with the highest affinity, antagonized the effect of Wnt3a and Wnt5a in different in vitro assays. Administration of UM206 to mice for 5 weeks, starting immediately after the induction of MI, reduced infarct expansion and increased the numbers of capillaries and myofibroblasts in the infarct area. Moreover, heart failure development was inhibited by this therapy.
Blocking of Frizzled signaling reduces infarct expansion and preserves cardiac function after MI. Our findings underscore the potential of Frizzled receptors as a target for pharmacotherapy of cardiac remodeling after MI.
控制心肌梗死后伤口愈合的分子途径尚未完全阐明。其中一条途径是 Wnt/Frizzled 途径。在这项研究中，我们评估了 Frizzled 作为心肌梗死后治疗的新靶点。这些 Frizzled 蛋白作为 Wnt 蛋白的受体，先前已被证明在愈合的梗死中表达。
Wnt/Frizzled 信号已研究了数十年，但迄今为止尚未描述干扰 Wnt 和 Frizzled 之间相互作用的合成配体。在这里，我们报告了选择 3 种源自 Wnt3a 和 Wnt5a 之间同源性较高区域的肽，它们作为 Frizzled 蛋白的拮抗剂。具有最高亲和力的肽 UM206 拮抗了不同体外测定中 Wnt3a 和 Wnt5a 的作用。在 MI 诱导后立即开始，用 UM206 对小鼠进行 5 周的治疗，可减少梗死面积的扩大，并增加梗死区域的毛细血管和肌成纤维细胞的数量。此外，这种治疗抑制了心力衰竭的发展。
阻断 Frizzled 信号可减少 MI 后梗死面积的扩大并维持心脏功能。我们的发现强调了 Frizzled 受体作为 MI 后心脏重构药物治疗的靶标。
