Isolinderalactone alleviates atherosclerosis by inhibiting NLRP3 inflammasome activation and inflammatory response in...

Area of Science:

• Pharmacology
• Immunology
• Biochemistry

Background:

• Atherosclerotic cardiovascular disease (ASCVD) is a major global health concern requiring novel therapeutic strategies.
• Isolinderalactone (ISO), a sesquiterpene from Lindera aggregata, exhibits anti-inflammatory properties.
• The therapeutic efficacy and mechanism of ISO in atherosclerosis (AS), a chronic inflammatory condition, remain largely unexplored.

Purpose of the Study:

• To investigate the therapeutic potential of Isolinderalactone (ISO) as an inhibitor of the NLRP3 inflammasome for managing atherosclerotic disease.
• To elucidate the molecular mechanisms underlying ISO's action on NLRP3 inflammasome activation in the context of AS.

Main Methods:

• In vivo studies utilized ApoE knockout mice on a high-fat diet to model atherosclerosis and assess ISO's therapeutic effects.
• In vitro studies employed bone marrow-derived macrophages (BMDMs) to determine ISO's mechanism of inhibiting NLRP3 inflammasome activation.
• Mass spectrometry and molecular docking analyses were performed to identify ISO's active binding sites on NLRP3.

Main Results:

• ISO significantly reduced atherosclerotic plaque formation by inhibiting NLRP3 inflammasome activation and associated inflammatory responses.
• Network pharmacology indicated ISO alleviates AS by suppressing the NOD-like receptor (NLR) pathway, reducing inflammatory mediators.
• ISO demonstrated dose-dependent inhibition of IL-1β secretion (IC50 = 2.882 μM) by blocking ASC oligomerization and NLRP3 inflammasome assembly.
• Mass spectrometry and docking simulations revealed ISO forms covalent bonds with NLRP3 at Cys470 in the NACHT domain.

Conclusions:

• Isolinderalactone (ISO) acts as a novel inhibitor of the NLRP3 inflammasome.
• ISO presents significant potential as a therapeutic candidate for treating atherosclerotic disease.