Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein...

Area of Science:

• Lipid biochemistry
• Cardiovascular science
• Protein modification

Background:

• Cardiovascular disease risk is linked to high-density lipoprotein (HDL) function, not just cholesterol levels.
• Isolevuglandins (IsoLGs) are reactive lipid dicarbonyls implicated in atherosclerosis.
• The impact of IsoLG modification on HDL function remains largely uninvestigated.

Purpose of the Study:

• To investigate the hypothesis that IsoLG modification of apolipoprotein A-I (apoA-I) impairs HDL function.
• To determine the structural and functional consequences of IsoLG modification on HDL.
• To evaluate the efficacy of pentylpyridoxamine (PPM) in preserving HDL function against IsoLG damage.

Main Methods:

• Quantification of IsoLG adducts in HDL from familial hypercholesterolemia patients and healthy controls.
• Assessment of IsoLG-lysine adducts in HDL exposed to myeloperoxidase.
• Evaluation of apoA-I and apoA-II cross-linking induced by IsoLG, succinylaldehyde, and 4-hydroxynonenal.
• Measurement of HDL size changes and HDL-mediated cholesterol efflux from macrophages via ABCA1.
• Assay of HDL's effect on lipopolysaccharide (LPS)-stimulated cytokine expression (IL-1β) in macrophages.
• Analysis of PPM's ability to reduce IsoLG adducts and rescue HDL function.

Main Results:

• HDL from familial hypercholesterolemia patients exhibited significantly higher IsoLG adducts than controls.
• Myeloperoxidase exposure elevated IsoLG-lysine adducts in HDL.
• PPM reduced IsoLG-lysine adducts by 67%, while its analogue pentylpyridoxine did not.
• IsoLG induced apoA-I/apoA-II cross-links at much lower concentrations than other dicarbonyls.
• IsoLG increased HDL size and significantly decreased HDL-mediated cholesterol efflux and HDL-apoA-I exchange.
• IsoLG exposure ablated HDL's anti-inflammatory capacity and increased IL-1β expression.

Conclusions:

• IsoLG modification of apoA-I detrimentally affects HDL structure and function.
• IsoLG impairs HDL's ability to facilitate cholesterol efflux and exert anti-inflammatory effects.
• PPM demonstrates potential as a therapeutic agent to mitigate IsoLG-induced HDL dysfunction.