Poloxamer 407 as a general lipase inhibitor: its implications in lipid metabolism and atheroma formation in C57BL/6 mice.
OBJECTIVE
The aims of this investigation were to determine if the activity of endothelial lipase was inhibited in vitro by the polymeric surfactant, poloxamer 407 (P-407), and to review the action of P-407 on the biological activity of several other critical lipases involved in lipid metabolism. The overall goal was to suggest a possible explanation for the observed dyslipidaemia and formation of aortic atherosclerotic lesions when present and previous findings, along with key findings proposed by others, were combined and reviewed in the context of the P-407-induced mouse model of atherogenesis.


RESULTS
Endothelial lipase was expressed using a recombinant adenovirus; subconfluent COS cells were exposed to recombinant adenoviruses and triglyceride lipase activity was determined using standard assay methods. It was demonstrated that P-407 inactivates endothelial lipase in vitro. Endothelial lipase was inhibited in vitro by P-407, with an IC50 of approximately 11.3 µm. It is suggested that one possible explanation for the eventual formation of aortic atherosclerotic lesions in the P-407-induced mouse model of atherogenesis may be related to the capacity of P-407 to inhibit the activity of several critical lipases involved in lipid metabolism.


CONCLUSIONS
The following physiological and biochemical processes are all observed in the P-407-induced mouse model of dyslipidaemia and atherosclerosis: inactivation of endothelial lipase (both in vitro and in vivo), hepatic lipase and lipoprotein lipase by P-407; reduced plasma levels of high-density lipoprotein cholesterol; no activation of either human or mouse peroxisome proliferator-activated receptor α (as well as peroxisome proliferator-activated receptor γ) in vitro or in vivo; increased plasma concentrations of soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1 and soluble E-selectin; and aortic atherosclerotic lesion formation following 12-16 weeks of P-407 administration (0.5 g/kg administered every 3 days by intraperitoneal injection). This biochemical-based pathway, or series of events, may contribute, in part, to the dyslipidaemia and eventual formation of aortic atherosclerotic lesions observed in the P-407-induced mouse model of atherogenesis.
Division of Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108-2718, USA. johnstont@umkc.edu
Thomas P
TP
Johnston
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D050171:Dyslipidemias / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000503:physiopathology; D020442:Poloxamer / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D047493:PPAR alpha; D047495:PPAR gamma; D013501:Surface-Active Agents; D019010:Vascular Cell Adhesion Molecule-1; D020442:Poloxamer; D018799:Intercellular Adhesion Molecule-1; D008049:Lipase; C498741:Lipg protein, mouse; D008071:Lipoprotein Lipase