Targeting KDM4C Prevents Heart Failure after Acute Myocardial Infarction Via Activation of SOS2

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Epigenetics

Background:

• Heart failure (HF) following acute myocardial infarction (AMI) remains a significant clinical challenge.
• Understanding the molecular pathways regulating cardiac function post-AMI is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of SOS2 in HF post-AMI.
• To elucidate the underlying molecular mechanisms involving KDM4C and PI3K/Akt signaling.

Main Methods:

• Utilized oxygen-glucose deprivation (OGD) in HL-1 cardiomyocytes and a mouse model of myocardial infarction (MI) via left anterior descending coronary artery ligation.
• Assessed SOS2 and KDM4C expression, H3K9Me3 modification, cardiomyocyte apoptosis, and inflammatory responses.
• Employed PI3K/Akt signaling inhibitor LY294002 and manipulated KDM4C and SOS2 levels through overexpression and knockdown.

Main Results:

• SOS2 was downregulated in cardiac tissues of AMI mice and OGD-treated cells.
• SOS2 activation of PI3K/Akt signaling alleviated cardiomyocyte apoptosis and inflammation.
• KDM4C overexpression upregulated SOS2 by demethylating H3K9Me3 on the SOS2 promoter.
• KDM4C deficiency exacerbated HF, while SOS2 knockdown counteracted KDM4C's protective effects.

Conclusions:

• KDM4C protects against HF post-AMI by upregulating SOS2 expression via epigenetic modification (H3K9Me3 demethylation).
• Restoration of SOS2 and subsequent activation of the PI3K/Akt pathway are key mechanisms mediating KDM4C's cardioprotective effects.
• Targeting the KDM4C-SOS2-PI3K/Akt axis may offer a novel therapeutic strategy for HF post-AMI.