Polycomb Repressive Complex 2 promotes atherosclerotic plaque vulnerability

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Epigenetics

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of death, driven by endothelial inflammation.
• Klf2 and Klf4 are anti-inflammatory transcription factors that counterbalance endothelial activation in ASCVD.
• Targeting vascular inflammation is crucial for developing effective ASCVD treatments.

Purpose of the Study:

• To identify key regulators of vascular inflammation and ASCVD progression.
• To investigate the role of Polycomb Repressive Complex 2 (PRC2) in endothelial inflammation and ASCVD.
• To evaluate the therapeutic potential of targeting PRC2 for ASCVD treatment.

Main Methods:

• Bioinformatic analysis to identify PRC2 as a direct suppressor of Klf2/4 transcription.
• Investigation of Notch signaling's role in reversing PRC2-mediated epigenetic modifications.
• Assessment of PRC2 activity in human ASCVD endothelium.
• Pharmacological inhibition of PRC2 using tazemetostat in a mouse model of established ASCVD.

Main Results:

• PRC2 was identified as a potent suppressor of the anti-inflammatory transcription factors Klf2/4.
• PRC2 activity was found to be elevated in human ASCVD endothelium.
• Treatment with the PRC2 inhibitor tazemetostat reduced ASCVD plaque progression by 50% and improved plaque stability markers in mice.

Conclusions:

• PRC2 is a critical determinant of vascular inflammation and a driver of ASCVD progression.
• Targeting PRC2, for example with tazemetostat, represents a promising therapeutic strategy for ASCVD.
• This study reveals a fundamental mechanism in vascular inflammation, suggesting potential treatments for ASCVD and other vascular inflammatory diseases.