心脏 Wnt5a 和 Wnt11 在压力超负荷下通过 FZD5 和 EGFR 信号的串扰促进纤维化。
Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload.
机构信息
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
出版信息
Cell Death Dis. 2021 Sep 25;12(10):877. doi: 10.1038/s41419-021-04152-2.
Progressive cardiac fibrosis accelerates the development of heart failure. Here, we aimed to explore serum Wnt5a and Wnt11 levels in hypertension patients, the roles of Wnt5a and Wnt11 in cardiac fibrosis and potential mechanisms under pressure overload. The pressure overload mouse model was built by transverse aortic constriction (TAC). Cardiac fibrosis was analyzed by Masson's staining. Serum Wnt5a or Wnt11 was elevated and associated with diastolic dysfunction in hypertension patients. TAC enhanced the expression and secretion of Wnt5a or Wnt11 from cardiomyocytes (CMs), cardiac fibroblasts (CFs), and cardiac microvascular endothelial cells (CMECs). Knockdown of Wnt5a and Wnt11 greatly improved cardiac fibrosis and function at 4 weeks after TAC. In vitro, shWnt5a or shWnt11 lentivirus transfection inhibited pro-fibrotic effects in CFs under mechanical stretch (MS). Similarly, conditional medium from stretched-CMs transfected with shWnt5a or shWnt11 lentivirus significantly suppressed the pro-fibrotic effects induced by conditional medium from stretched-CMs. These data suggested that CMs- or CFs-derived Wnt5a or Wnt11 showed a pro-fibrotic effect under pressure overload. In vitro, exogenous Wnt5a or Wnt11 activated ERK and p38 (fibrotic-related signaling) pathway, promoted the phosphorylation of EGFR, and increased the expression of Frizzled 5 (FZD5) in CFs. Inhibition or knockdown of EGFR greatly attenuated the increased FZD5, p-p38, and p-ERK levels, and the pro-fibrotic effect induced by Wnt5a or Wnt11 in CFs. Si-FZD5 transfection suppressed the increased p-EGFR level, and the fibrotic-related effects in CFs treated with Wnt5a or Wnt11. In conclusion, pressure overload enhances the secretion of Wnt5a or Wnt11 from CMs and CFs which promotes cardiac fibrosis by activation the crosstalk of FZD5 and EGFR. Thus, Wnt5a or Wnt11 may be a novel therapeutic target for the prevention of cardiac fibrosis under pressure overload.
心肌纤维化的进行性发展加速了心力衰竭的发生。在这里，我们旨在探索高血压患者血清 Wnt5a 和 Wnt11 水平，探讨 Wnt5a 和 Wnt11 在心脏压力超负荷下心肌纤维化中的作用及其潜在机制。通过横主动脉缩窄（TAC）构建压力超负荷小鼠模型。采用 Masson 染色分析心肌纤维化。高血压患者血清 Wnt5a 或 Wnt11 水平升高，与舒张功能障碍相关。TAC 增强了心肌细胞（CMs）、心脏成纤维细胞（CFs）和心脏微血管内皮细胞（CMECs）中 Wnt5a 或 Wnt11 的表达和分泌。TAC 后 4 周，敲低 Wnt5a 和 Wnt11 可显著改善心肌纤维化和功能。在体外，机械拉伸（MS）下，shWnt5a 或 shWnt11 慢病毒转染抑制 CFs 的促纤维化作用。同样，转染 shWnt5a 或 shWnt11 慢病毒的拉伸 CM 条件培养基显著抑制了由拉伸 CM 条件培养基诱导的促纤维化作用。这些数据表明，CM 或 CF 来源的 Wnt5a 或 Wnt11 在压力超负荷下表现出促纤维化作用。在体外，外源性 Wnt5a 或 Wnt11 激活 ERK 和 p38（纤维化相关信号通路），促进 CFs 中 EGFR 的磷酸化，并增加 Frizzled 5（FZD5）的表达。EGFR 的抑制或敲低可显著减弱 Wnt5a 或 Wnt11 诱导的 CFs 中 FZD5、p-p38 和 p-ERK 水平的增加以及促纤维化作用。Si-FZD5 转染抑制了 Wnt5a 或 Wnt11 处理的 CFs 中 p-EGFR 水平的增加和纤维化相关作用。总之，压力超负荷增强了 CMs 和 CFs 中 Wnt5a 或 Wnt11 的分泌，通过激活 FZD5 和 EGFR 的串扰促进心肌纤维化。因此，Wnt5a 或 Wnt11 可能是压力超负荷下预防心肌纤维化的新治疗靶点。
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