The effect of poloxamer 407 on the functional properties of HDL in mice

Abstract

Objectives: There is an inverse relationship between high-density lipoprotein (HDL) and heart disease. HDL possesses not only both antioxidant and anti-inflammatory properties, but also anti-thrombotic and endothelial function-promoting qualities. However, it is not only the serum concentration of HDL that is important, but also the 'functional' quality of the HDL. The objective was to determine the functional status of HDL in a well-established mouse model of dyslipidaemia and atherosclerosis induced by the administration of a block copolymer (poloxamer 407; P-407).

Methods: C57BL/6 mice were administered a single intraperitoneal dose of P-407 (0.5g/kg) and blood was collected at 24h post-dosing. HDL was isolated from controls (control HDL) and P-407-treated (P-407 HDL) mice and used to test its anti-inflammatory properties in vitro. Additionally, antioxidant enzymes associated with HDL, namely, platelet activating factor-acetylhydrolase (PAF-AH) and paraoxonase (PON), were evaluated for any potential reduction in their biological activity.

Key findings: A single injection of P-407 in C57BL/6 mice resulted in a marked decrease in the levels of HDL-cholesterol and phospholipids. HDL particle size significantly increased, primarily due to remodelling of HDL with triglyceride. It was demonstrated that (i) long-chain saturated fatty acids were higher and the n-3/n-6 fatty acid ratio was significantly lower for P-407 HDL compared with control HDL, and (ii) P-407 HDL lost its capacity to inhibit tumour necrosis factor-α (TNF-α)-induced vascular cell adhesion molecule-1 (VCAM-1) expression compared with control HDL. Additionally, P-407 HDL was not able to neutralize lipopolysaccharide and inhibit subsequent TNF-α production compared with control HDL. The biological activity of platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase (PON) decreased in direct proportion to the circulating levels of both HDL-cholesterol and apolipoprotein (apoA-1).

Conclusions: Combination of previously reported findings in P-407-treated mice, such as (i) production of both oxidized LDL and malondialdehyde, and (ii) profound elevations in the soluble forms of intercellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin, with the present results, would strongly suggest that HDL in P-407-treated mice is rendered dysfunctional. Thus, these findings help to explain why P-407-treated mice begin to form aortic atherosclerotic lesions about one month after initiating P-407 treatment.