University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Sci Rep. 2021 Sep 6;11(1):17722. doi: 10.1038/s41598-021-97176-9.
Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.
Wnt/β-catenin 信号在心肌梗死后（MI）在心脏中被激活。本研究旨在探讨β-catenin 缺失是否会影响 MI 后离子通道基因改变和室性心动过速（VT）。通过在野生型（WT）和心肌细胞特异性β-catenin 敲除（KO）小鼠的左前降支永久性结扎来诱导 MI。KO 小鼠在 MI 后 8 周时对 VT 的易感性降低（WT 为 77%，KO 为 18%），与疤痕面积减小和心室扩张减弱有关。对 MI 后心肌组织和纯化的心肌细胞进行 qPCR 分析表明，Wnt 通路基因在边界和梗死区域上调，包括 Wnt 配体（如 Wnt4）和受体（如 Fzd1 和 Fzd2）。在 MI 后 1 周时，WT 心脏中的心脏钠离子通道基因（Scn5a）转录物减少，但 KO 心脏中没有减少，这与先前的研究一致，表明 Wnt/β-catenin 信号抑制 Scn5a。在 MI 后 8 周时，Wnt 基因下降，Scn5a 恢复到接近假手术水平，WT 和 KO 小鼠之间 K 通道基因下调没有差异。本研究表明，在 MI 后慢性期，心肌细胞特异性β-catenin 缺失的小鼠 VT 易感性降低主要是通过减弱结构重塑来实现的，而不是通过离子通道基因改变。
