Internal Medicine III, University Hospital Heidelberg, 69120 Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg-Mannheim, 69120 Heidelberg, Germany.
Int J Mol Sci. 2022 Oct 14;23(20):12252. doi: 10.3390/ijms232012252.
Wnt (a portmanteau of and ) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 on MI healing. Ischemia/reperfusion (I/R) injury was induced in mice and Wnt signaling was inhibited by oral administration of the porcupine inhibitor LGK-974. The transcriptome was analyzed from infarcted tissue by using RNA sequencing analysis. The inflammatory response after I/R was evaluated by flow cytometry. Heart function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Transcriptome and gene set enrichment analysis revealed a modulation of the inflammatory response upon administration of the Wnt secretion inhibitor LGK-974 following I/R. In addition, LGK-974-treated animals showed an attenuated inflammatory response and improved heart function. In an in vitro model of hypoxic cardiomyocyte and monocyte/macrophage interaction, LGK974 inhibited the activation of Wnt signaling in monocytes/macrophages and reduced their pro-inflammatory phenotype. We here show that Wnt signaling affects inflammatory processes after MI. The Wnt secretion inhibitor LGK-974 appears to be a promising compound for future immunomodulatory approaches to improve cardiac remodeling after MI.
Wnt（和的混合词）信号在成人心脏中基本处于静止状态。然而，越来越多的证据表明，它在心肌梗死（MI）后的愈合过程中重新激活。我们在这里测试了 Wnt 分泌抑制剂 LGK-974 在 MI 愈合中的治疗潜力。通过口服使用刺猬抑制剂 LGK-974 在小鼠中诱导缺血/再灌注（I/R）损伤，抑制 Wnt 信号。通过 RNA 测序分析从梗塞组织中分析转录组。通过流式细胞术评估 I/R 后的炎症反应。通过超声心动图评估心脏功能，通过 Masson 三色染色评估纤维化。转录组和基因集富集分析显示，在用 Wnt 分泌抑制剂 LGK-974 处理后，I/R 后炎症反应受到调节。此外，LGK-974 处理的动物表现出炎症反应减弱和心脏功能改善。在缺氧心肌细胞和单核细胞/巨噬细胞相互作用的体外模型中，LGK974 抑制了单核细胞/巨噬细胞中 Wnt 信号的激活，并降低了它们的促炎表型。我们在这里表明，Wnt 信号会影响 MI 后的炎症过程。Wnt 分泌抑制剂 LGK-974 似乎是一种有前途的化合物，可用于未来改善 MI 后心脏重塑的免疫调节方法。
