Wnt4 is crucial for cardiac repair by regulating mesenchymal-endothelial transition via the phospho-JNK/JNK

Abstract

Rational: Wnt4 plays a critical role in development and is reactivated during fibrotic injury; however, the role of Wnt4 in cardiac repair remains unclear. In this study, our aim was to clarify the pathophysiological role and mechanisms of Wnt4 following acute cardiac ischemic reperfusion injury. Methods and results: We investigated the spatio-temporal expression of Wnt4 following acute cardiac ischemic reperfusion injury and found that Wnt4 was upregulated as an early injury response gene in cardiac fibroblasts near the injury border zone and associated with mesenchymal-endothelial transition (MEndoT), a beneficial process for revascularizing the damaged myocardium in cardiac repair. Using ChIP assay and in vitro and in vivo loss- and gain-of-function, we demonstrated that Wnt4 served as a crucial downstream target gene of p53 during MEndoT. Wnt4 knockdown in cardiac fibroblasts led to decreased MEndoT and worsened cardiac function. Conversely, Wnt4 overexpression in cardiac fibroblasts induced MEndoT in these cells via the phospho-JNK/JNK signaling pathway; however, both the p53 and Wnt4 protein levels were dependent on the β-catenin signaling pathway. JNK activation plays a critical role in the induction of MEndoT and is crucial for Wnt4 regulated MEndoT. Moreover, Wnt4 overexpression specifically in cardiac fibroblasts rescued the cardiac function worsening due to genetic p53 deletion by decreasing fibrosis and increasing MEndoT and vascular density. Conclusion: Our study revealed that Wnt4 plays a pivotal role in cardiac repair with involvement of phospho-JNK mediated MEndoT and is a crucial gene for cardiac fibroblast-targeted therapy in heart disease.

TEA domain transcription factor 1 (TEAD1) induces cardiac fibroblasts cells remodeling through BRD4/Wnt4 pathway

“… 32 , 33 Furthermore, its activation occurs in instances of fibrotic injury, including those associated with cardiovascular disease, chronic kidney fibrosis, and skin wounds. 34 – 36 Wnt4 facilitates the differentiation of myofibroblasts in interstitial pericytes and fibroblasts through the canonical Wnt/β-catenin signalling pathway during renal fibrosis. 37 Our research offers fresh perspectives on unraveling the mechanism underlying the role played by Wnt4 in TEAD1-regulated CFs differentiation.…”

ScRNA-seq and spatial transcriptomics: exploring the occurrence and treatment of coronary-related diseases starting from development

“…Given the activity of the p53 transcription factor in various cellular stresses, researchers have explored whether p53 is involved in phenotypic changes in fibroblasts under myocardial infarction stress. They demonstrated that the transcription factor P53 could participate in the regulation of fibroblast mesenchymal-endothelial transition by introducing P53-binding primers ( 61 ). Dong et al used chromatin immunoprecipitation and gene knockout methods to demonstrate that Wnt4 plays an important role in fibroblast transformation after cardiac injury.…”

“…They found that Wnt4 was a key downstream target gene in the regulation of fibroblast mesenchymal-endothelial transition by the transcription factor P53. Under the action of the transcription factor P53, Wnt4 is overexpressed in cardiac fibroblasts and induces fibroblast mesenchymal-endothelial transition through the phosphorylation-JNK/JNK signaling pathway ( 61 ). Although some researchers thought that the method of labeling fibroblasts in their study was inaccurate, later investigators demonstrated that at least some fibroblasts undergo this transition ( 62 ).…”