Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

Area of Science:

• Cardiovascular Science
• Inflammation Biology
• Pharmacology

Background:

• Atherosclerosis is a leading cause of global mortality, driven by chronic inflammation and cholesterol accumulation.
• Current treatments for atherosclerosis face limitations despite advancements.
• Retention of apolipoprotein B lipoproteins leads to free cholesterol overload and triggers inflammatory responses.

Purpose of the Study:

• To investigate the efficacy of 2-hydroxypropyl-β-cyclodextrin (CD) in preventing and reversing atherosclerosis.
• To elucidate the mechanisms underlying CD's effects on cholesterol metabolism and inflammation in atherosclerosis.

Main Methods:

• Treatment of murine atherosclerosis models with CD.
• Analysis of atherosclerotic plaque size, cholesterol crystal load, and inflammatory markers.
• Investigation of oxysterol production and liver X receptor (LXR) activation.
• Assessment of cholesterol efflux and reverse cholesterol transport.

Main Results:

• CD treatment significantly reduced atherosclerotic plaque size and cholesterol crystal burden in mice.
• CD promoted plaque regression even under a cholesterol-rich diet.
• Mechanistically, CD enhanced oxysterol production and LXR-mediated cholesterol efflux, leading to anti-inflammatory effects.
• CD-induced LXR agonism was crucial for its anti-atherosclerotic and anti-inflammatory actions.

Conclusions:

• 2-hydroxypropyl-β-cyclodextrin (CD) demonstrates significant potential in preventing and reversing atherosclerosis.
• CD's therapeutic effects are mediated by enhanced cholesterol efflux and LXR activation.
• CD's established safety profile in humans suggests its clinical utility for treating atherosclerosis and cardiovascular disease.