4.5 Article

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

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DOI: 10.1007/s12265-023-10472-9

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Myocardial infarction; CAV1; Bone marrow-derived mesenchymal stem cells; Extracellular vesicles

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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.
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.

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