CAV1 Protein Encapsulated in Mouse BMSC-Derived Extracellular Vesicles Alleviates Myocardial Fibrosis Following Myocardial Infarction by Blocking the TGF-β1/SMAD2/c-JUN Axis

Extracellular vesicles (EVs) derived from mouse bone marrow mesenchymal stem cells (mBMSCs) convey the CAV1 protein, influencing the TGF-beta 1/SMAD2/c-JUN pathway and thus the molecular mechanisms underlying myocardial fibrosis (MF) post-myocardial infarction (MI). Through various experimental methods, including transmission electron microscopy, Nanosight analysis, Western blot, ELISA, and qRT-PCR, we isolated, purified, and identified EVs originating from mBMSCs. Bioinformatics and experimental findings show a reduced expression of CAV1 in myocardial fibrosis tissue. Furthermore, our findings suggest that mBMSC-EVs can deliver CAV1 to cardiac fibroblasts (CFs) and that silencing CAV1 in mBMSC-EVs promotes CF fibrosis. In vivo studies further corroborated these findings. In conclusion, mBMSC-EVs mitigate myocardial fibrosis in MI mice by delivering the CAV1 protein, inhibiting the TGF-beta 1/SMAD2/c-JUN pathway.Graphical AbstractMolecular mechanism of mBMSC-EVs-CAV1-mediated TGF-beta 1/SMAD2/c-JUN axis in inhibiting cardiac fibroblast differentiation to improve MF after MI. mBMSC-EVs deliver CAV1 protein to CFs where the protein expression of CAV1 is upregulated upon hypoxia conditions. The TGF-beta 1/SMAD2 signaling pathway downstream of CAV1 is consequently inactivated, the transcription of c-JUN is inhibited, and transcription of SMAD2/c-JUN transcription complex target genes alpha-SMA and Collagen I is reduced. By this mechanism, CF fibrosis and apoptosis are suppressed in vitro and MF is ameliorated in MI mice.

Automated summary

Extracellular vesicles derived from mouse bone marrow mesenchymal stem cells (mBMSCs) deliver the CAV1 protein, which influences the TGF-beta 1/SMAD2/c-JUN pathway and plays a role in the molecular mechanisms underlying myocardial fibrosis post-myocardial infarction. The study showed a reduced expression of CAV1 in myocardial fibrosis tissue. Furthermore, mBMSC-EVs were found to deliver CAV1 to cardiac fibroblasts and silencing CAV1 in mBMSC-EVs promoted fibrosis in cardiac fibroblasts. In vivo studies supported these findings, demonstrating that mBMSC-EVs mitigate myocardial fibrosis by delivering CAV1 protein and inhibiting the TGF-beta 1/SMAD2/c-JUN pathway.