Connexin 43 dephosphorylation mediates the Dchs1/YAP/TEAD signaling pathway to impact cardiac fibrosis
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ABSTRACT:
PROVIDER: PRJNA1048890 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27106000_1.fastq.gz | Fastqsanger.gz | |||
| SRR27106000_2.fastq.gz | Fastqsanger.gz | |||
| SRR27106001_1.fastq.gz | Fastqsanger.gz | |||
| SRR27106001_2.fastq.gz | Fastqsanger.gz | |||
| SRR27106002_1.fastq.gz | Fastqsanger.gz |
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Project description:The gap junction protein connexin 43 (Cx43) has been implicated in the development of cardiac fibrosis. We found that Cx43 dephosphorylation at serine 282 (S282) is related to cardiomyocyte apoptosis and arrhythmias in hearts damaged by ischemia/reperfusion. Here, we investigated the effect of Cx43 S282 phosphorylation on fibrosis. We found a decrease in Cx43 S282 phosphorylation in transforming growth factor beta-1 (TGF-β)-induced fibrosis in fibroblasts and an angiotensin II-induced rat model. We transferred a lentivirus with S282A (alanine) into cardiac fibroblasts and an adenovirus with S282A into the hearts of rats. We found that the Cx43 S282A mutation caused fibrosis in cardiac fibroblasts and in the hearts of rats, which suggested that the phosphorylation of Cx43 S282 is important in the development of fibrosis. Furthermore, mRNA sequencing showed that Cx43 dephosphorylation at S282 increased the expression of Dchs1, and Dchs1 inhibited Yes-associated protein (YAP) phosphorylation, subsequently activating the YAP/TEAD signaling pathway and increasing the development of fibrosis. This study suggests that the phosphorylation of Cx43 S282 could be an effective antifibrotic target in cardiac fibroblasts, indicating a novel mechanism and a molecular target that might be promising for the treatment of cardiac fibrosis.
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Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.
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