Transcription factor EB affects the thrombospondin-1 /focal adhesion pathway and inhibits cardiac fibroblast transformation following early acute myocardial infarction

Acute myocardial infarction (AMI) is currently the most common cause of fibrosis in the heart and has been reported to be closely associated with heart failure (HF). The transformation of cardiac fibroblasts (CFs) into myofibroblasts is key to the process of cardiac fibrosis, where CFs serve as the main effector cells. Accumulating evidence suggests that focal adhesions (FAs) regulate the transformation of CFs. Furthermore, transcription factor EB (TFEB) upregulates the transcriptional expression of genes involved in lysosome and autophagosome biogenesis following AMI. This study investigated whether TFEB directly targets and inhibits the activation of CFs and elucidated the underlying pathomechanisms. We performed a transcriptome analysis employing RNA sequencing in R26-LSL-TFEB [+/+]; Acta2-cre mice. Our study presents the first detailed RNA expression profile of CFs following AMI, demonstrating that TFEB regulates the expression of several RNAs involved in the transformation of CFs, including those associated with extracellular matrix (ECM) receptor pathways and FAs. Thrombospondin-1 (Thbs1) mRNA and protein were markedly upregulated in CFs. Bioinformatic prediction and chromatin immunoprecipitation identified that TFEB binds to the Thbs1 promoter. Experimental validation at both RNA and protein levels demonstrated that TFEB affects the binding of Thbs1 to its receptors and the activation of FAs. Concurrently, TFEB downregulates the expression of α-smooth muscle actin (α-SMA). Taken together, our results highlight that targeting the regulation of Thbs1/FA signaling in CFs via TFEB may be a promising therapeutic approach for cardiac fibrosis.