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Cardiomyocyte-specific Peli1 contributes to the pressure overload-induced cardiac fibrosis through
Chao Tang1,2, Yu-Xing Hou1, Peng-Xi Shi1
1Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Insights
Peli1 in cardiomyocytes promotes cardiac fibrosis by releasing miR-494-3p via exosomes, which activate cardiac fibroblasts. Deleting Peli1 in myocytes reduces fibrosis, suggesting exosomal miRNAs as a therapeutic target for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiac fibrosis is a key factor in pressure overload-induced heart failure.
- Communication between cardiomyocytes and cardiac fibroblasts is critical in heart failure progression.
- Exosomes carrying microRNAs (miRNAs) mediate communication between cardiomyocytes and fibroblasts.
Purpose of the Study:
- To investigate the role of Peli1 in cardiomyocytes (CMs) in regulating cardiac fibroblast (CF) activation via exosomal miRNAs.
- To determine if Peli1 in CMs contributes to pressure overload-induced cardiac fibrosis.
- To explore the potential of targeting the Peli1-exosome-miRNA pathway for treating cardiac fibrosis.
Main Methods:
- Conditional deletion of Peli1 in CMs in a pressure overload mouse model.
- Isolation and characterization of exosomes from mechanical stretch-induced CMs.
- miRNA microarray and quantitative PCR (qPCR) to analyze exosomal miRNA content.
- Western blot analysis to assess protein phosphorylation and signaling pathways (PTEN, AKT, SMAD2/3, ERK).
Main Results:
- Conditional deletion of Peli1 in CMs ameliorated pressure overload-induced cardiac fibrosis.
- Exosomes from mechanical stretch-induced wild-type CMs promoted CF activation, while exosomes from Peli1-deficient CMs did not.
- miR-494-3p was upregulated in exosomes from wild-type CMs and downregulated in exosomes from Peli1-deficient CMs.
- Peli1 promoted miR-494-3p expression in CMs via NF-κB/AP-1 signaling.
- miR-494-3p activated CFs by inhibiting PTEN and enhancing AKT, SMAD2/3, and ERK phosphorylation.
Conclusions:
- Peli1 in cardiomyocytes drives myocardial fibrosis through exosomal miR-494-3p under pressure overload conditions.
- This pathway involves Peli1-mediated upregulation of miR-494-3p in CMs, followed by exosome-mediated transfer to CFs, promoting their activation.
- Targeting the Peli1-exosome-miR-494-3p axis offers a potential therapeutic strategy for cardiac fibrosis.
Abstract:
Cardiac fibrosis is an essential pathological process in pressure overload (PO)-induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA-mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1-/- MS-Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR-494-3p was increased in WT MS-Exos while being down regulated in Peli1-/- MS-Exos. Mechanistically, Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in CMs, and then miR-494-3p induced CFs activation by inhibiting PTEN and amplifying the phosphorylation of AKT, SMAD2/3, and ERK. Collectively, our study suggests that CMs Peli1 contributes to myocardial fibrosis via CMs-derived miR-494-3p-enriched exosomes under PO, and provides a potential exosomal miRNA-based therapy for cardiac fibrosis.
