Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1...

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Nutritional Science

Background:

• Atherosclerosis is a major global cause of cardiovascular disease.
• Endothelial ferroptosis is increasingly recognized as a critical mechanism in vascular injury.
• Dietary flavonoids, like quercetin (QCT), possess antioxidant properties with potential therapeutic benefits.

Purpose of the Study:

• To investigate if quercetin (QCT) protects against atherosclerosis-associated endothelial dysfunction.
• To determine if QCT modulates endothelial ferroptosis.
• To elucidate the molecular mechanisms underlying QCT's protective effects, focusing on the PACS2-HMOX-1 pathway.

Main Methods:

• ApoE[Formula: see text] mice on a high-fat diet were treated with QCT or ferrostatin-1 to assess plaque burden and stability.
• Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (Ox-LDL) with or without QCT to measure ferroptosis markers (ROS, Fe[Formula: see text], HMOX-1).
• Functional assays evaluated endothelial barrier integrity and monocyte adhesion; gene modulation studies examined phosphofurin acidic cluster sorting protein 2 (PACS2) expression.

Main Results:

• QCT treatment significantly reduced aortic plaque area, necrotic core size, and macrophage infiltration, while improving plaque stability in mice.
• In vitro, QCT suppressed Ox-LDL-induced ferroptosis by decreasing reactive oxygen species (ROS) and iron (Fe[Formula: see text]) levels and downregulating heme oxygenase-1 (HMOX-1).
• QCT restored endothelial integrity and reduced monocyte adhesion, mechanistically by upregulating PACS2 expression suppressed by Ox-LDL.

Conclusions:

• Quercetin (QCT) demonstrates significant protective effects against atherosclerosis by mitigating endothelial ferroptosis.
• The mechanism involves QCT's modulation of the PACS2-HMOX-1 ferroptosis pathway.
• QCT is identified as a promising dietary antioxidant for managing atherosclerosis and related vascular dysfunction.