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β-catenin ameliorates myocardial infarction by preventing YAP-associated apoptosis

Objective: To explore whether the effect of β-catenin on MI and MI-induced cardiomyocyte apoptosis is YAP-dependent.

Methods: The authors established an MI rat model by ligating the anterior descending branch of the left coronary artery, and an MI cell model by treating cardiomyocytes with H2O2.

Results: β-catenin downregulation was observed in MI cardiac tissues and in H2O2-treated cardiomyocytes. Lentiviral-CTNNB1 was administered to MI rats to upregulate β-catenin expression in MI cardiac tissue. β-catenin recovery reduced the myocardial infarct area, fibrosis, and apoptotic cell death in MI rats. H2O2 treatment attenuated cell viability and induced cell death in cardiomyocytes, whereas β-catenin overexpression partially reversed these changes. Moreover, H2O2 treatment caused the deactivation of Yes-Associated Protein (YAP), as detected by increased YAP phosphorylation and reduced the nuclear localization of YAP. Upregulation of β-catenin expression reactivated YAP in H2O2-treated cardiomyocytes. Reactivation of YAP was achieved by administration of Mitochonic Acid-5 (MA-5) to H2O2-treated cardiomyocytes, and deactivation of YAP by CIL56 treatment in β-catenin-overexpressing H2O2-treated cardiomyocytes. MA-5 administration increased cell viability and repressed apoptosis in H2O2-treated cardiomyocytes, whereas CIL56 treatment counteracted the effects of β-catenin overexpression on cell survival and apoptosis.

Conclusions: The present data indicate that β-catenin and YAP are effective treatment targets for MI, blocking the apoptotic death of cardiomyocytes.

 

Comments:

The study aimed to investigate the potential involvement of Yes-Associated Protein (YAP) in the effects of β-catenin on myocardial infarction (MI) and MI-induced cardiomyocyte apoptosis. The researchers utilized both in vivo and in vitro models to examine the effects of β-catenin modulation on MI and cardiomyocyte apoptosis and assessed the relationship between β-catenin and YAP.

In the in vivo model, MI was induced in rats by ligating the anterior descending branch of the left coronary artery. The researchers observed a downregulation of β-catenin in the cardiac tissues of rats with MI. To upregulate β-catenin expression, they administered lentiviral-CTNNB1 (which encodes for β-catenin) to the MI rats. This resulted in the recovery of β-catenin expression and led to a reduction in the myocardial infarct area, fibrosis, and apoptotic cell death in the MI rats.

In the in vitro model, the researchers treated cardiomyocytes with H2O2 to mimic the cellular effects of MI. They observed that H2O2 treatment attenuated cell viability and induced cell death in the cardiomyocytes. However, when β-catenin was overexpressed in the H2O2-treated cardiomyocytes, these detrimental effects were partially reversed, indicating a protective role of β-catenin against H2O2-induced damage.

Furthermore, the researchers investigated the relationship between β-catenin and YAP. They found that H2O2 treatment caused the deactivation of YAP, as evidenced by increased YAP phosphorylation and reduced nuclear localization of YAP in cardiomyocytes. However, when β-catenin expression was upregulated, YAP was reactivated in the H2O2-treated cardiomyocytes. This suggests that β-catenin plays a role in the regulation of YAP activity.

To further support the involvement of YAP, the researchers used Mitochonic Acid-5 (MA-5) and CIL56, which are known modulators of YAP activity. Treatment with MA-5, which activates YAP, increased cell viability and reduced apoptosis in H2O2-treated cardiomyocytes. Conversely, treatment with CIL56, which deactivates YAP, counteracted the effects of β-catenin overexpression on cell survival and apoptosis in H2O2-treated cardiomyocytes.

In conclusion, the study suggests that β-catenin and YAP are potential treatment targets for MI, as they are involved in blocking the apoptotic death of cardiomyocytes. The upregulation of β-catenin expression and subsequent reactivation of YAP were associated with improved outcomes in both in vivo and in vitro models of MI. These findings highlight the potential therapeutic importance of targeting the β-catenin/YAP pathway in the context of MI and cardiomyocyte apoptosis.

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