Connexin 43 dephosphorylation mediates the Dchs1/YAP/TEAD signaling pathway to induce cardiac fibrosis
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View abstract on PubMed
Summary
This summary is machine-generated.Phosphorylation of connexin 43 (Cx43) at serine 282 (S282) inhibits cardiac fibrosis by activating the Hippo signaling pathway. Targeting Cx43 S282 phosphorylation offers a novel therapeutic strategy for treating cardiac fibrosis.
Area Of Science
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background
- Connexin 43 (Cx43), a gap junction protein, is implicated in cardiac fibrosis development.
- Cx43 dephosphorylation at serine 282 (S282) is linked to cardiomyocyte apoptosis and arrhythmias post-ischemia/reperfusion.
- This study investigates the specific role of Cx43 S282 phosphorylation in cardiac fibrosis.
Purpose Of The Study
- To elucidate the role of Cx43 S282 phosphorylation in the pathogenesis of cardiac fibrosis.
- To identify the molecular mechanisms underlying Cx43 S282 phosphorylation's effect on cardiac fibrosis.
- To explore Cx43 S282 phosphorylation as a potential therapeutic target for cardiac fibrosis.
Main Methods
- Established in vivo (angiotensin II) and in vitro (TGF-β1) cardiac fibrosis models.
- Examined Cx43 S282 phosphorylation levels in fibrosis models.
- Utilized lentiviral and adenoviral vectors for Cx43 S282 phosphorylation manipulation in vitro and in vivo.
- Performed mRNA sequencing and Gene Set Enrichment Analysis (GSEA) to identify affected signaling pathways.
- Validated the role of the Hippo signaling pathway in Cx43 S282 phosphorylation-mediated fibrosis.
Main Results
- Reduced Cx43 S282 phosphorylation observed in both in vivo and in vitro cardiac fibrosis models.
- Mutation of Cx43 S282 to a non-phosphorylatable form (S282A) exacerbated fibrosis markers.
- Increased Cx43 S282 phosphorylation demonstrated an antifibrotic effect, inhibiting fibrosis development.
- mRNA sequencing revealed the involvement of the Hippo signaling pathway.
- Cx43 S282 phosphorylation activated Dchs1, leading to YAP phosphorylation and inhibition of the YAP/TEAD pathway, thereby suppressing fibrosis.
Conclusions
- Cx43 S282 phosphorylation acts as a critical antifibrotic factor in cardiac fibroblasts.
- The Hippo signaling pathway is a key mediator of Cx43 S282 phosphorylation's antifibrotic effects.
- Phosphorylation of Cx43 S282 represents a promising molecular target for novel cardiac fibrosis therapies.
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