Downregulation of circ-ZNF609 Promotes Heart Repair by Modulating RNA N⁶-Methyladenosine-Modified Yap Expression

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Epigenetics

Background:

• Circular RNAs (circRNAs) play significant roles in various pathophysiological processes.
• The specific function and mechanisms of circ-ZNF609 in cardiac regulation are not well understood.

Purpose of the Study:

• To investigate the role of circ-ZNF609 in myocardial ischemia/reperfusion (I/R) injury and remodeling.
• To elucidate the underlying molecular mechanisms by which circ-ZNF609 affects cardiac function.

Main Methods:

• In vivo studies using animal models of myocardial I/R injury.
• In vitro experiments on cardiomyocytes to assess cell survival and proliferation.
• Analysis of signaling pathways including Hippo-YAP and Akt.
• Investigation of N⁶-methyladenosine (m⁶A) modification and its impact on circ-ZNF609 and YAP mRNA regulation.

Main Results:

• Circ-ZNF609 expression is upregulated during myocardial I/R remodeling.
• Knockdown of circ-ZNF609 demonstrated protective effects against acute I/R injury and attenuated left ventricle dysfunction.
• In vitro, circ-ZNF609 modulated cardiomyocyte survival and proliferation by influencing the Hippo-YAP and Akt signaling pathways.
• N⁶-methyladenosine modification was found to be involved in circ-ZNF609's regulation of YAP.
• Circ-ZNF609 knockdown reduced YTHDF3 expression and altered YAP mRNA accessibility to YTHDF1 and YTHDF2.

Conclusions:

• Circ-ZNF609 plays a detrimental role in myocardial I/R injury and remodeling.
• Targeting circ-ZNF609, potentially through knockdown, represents a promising therapeutic strategy for mitigating myocardial I/R injury.
• The mechanism involves the modulation of Hippo-YAP and Akt signaling, with N⁶-methyladenosine modification playing a role in YAP regulation.