摘要
Cardiac fibroblasts(CFs)are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure(HF).TEAD1 has been shown to be essential for heart development and homeostasis.However,fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood.Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction(TAC)and Ang-l infusion.Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload.Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs-and myofibroblasts-specific Cre mice.Echocardiographic and histological analyses demonstrated that CFs-and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor,VT103,ameliorated TAC-induced cardiac remodeling.Mechanistically,RNA-seq and ChiP-seq analysis identified Wnt4 as a novel TEAD1 target.TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway,and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression.Furthermore,coimmunoprecipitation combined with mass spectrometry,chromatin immunoprecipitation,and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4,leading to the binding and activation of the Wnt4 promoter.In conclusion,TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signallingpathway.
基金
supported by the China National Funds for Young Scientists(grant number 82000309 to Shuai Song,82200290 to Yongchao Zhao)
the Shanghai Sailing Program(grant number 20YF1429600 to Shuai Song),Basic Science Center Project(grant number T2288101 to Junbo Ge)
the National Natural Science Foundation(grant number 82130010 to Aijun Sun)
the Shanghai Clinical Research Center for Interventional Medicine(grant number 19MC1910300 to Junbo Ge)
Fuqing Scholar of Fudan University,Shanghai Medical School(grant number FQXZ202204B to Zihang Huang).
