Aspirin inhibits formation of cholesterol rafts in fluid lipid membranes

• Published in: Biochimica et biophysica acta Vol. 1848; no. 3; pp. 805 - 812
• Main Authors: Alsop, Richard J., Toppozini, Laura, Marquardt, Drew, Kučerka, Norbert, Harroun, Thad A., Rheinstädter, Maikel C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2015
• Subjects: 1,2-Dipalmitoylphosphatidylcholine - chemistry; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aspirin; Aspirin - chemistry; Aspirin - pharmacology; Aspirin–cholesterol interaction; Calorimetry, Differential Scanning; Cell Membrane - chemistry; Cell Membrane - drug effects; Cholesterol; Cholesterol - chemistry; Cholesterol rafts; Humans; Kinetics; Lipid Bilayers - chemistry; Lipid membranes; Membrane Fluidity; Membrane Lipids - chemistry; Membrane Microdomains - chemistry; Models, Chemical; Models, Molecular; Molecular Structure; Neutron Diffraction; L-B; Aspirin; Aspirin–cholesterol interaction; COX; Cholesterol; ASA; Lipid membranes; TFE; Cholesterol rafts; DSC; RH; PG; DPPC
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2014.11.023

Aspirin and other non-steroidal anti-inflammatory drugs have a high affinity for phospholipid membranes, altering their structure and biophysical properties. Aspirin has been shown to partition into the lipid head groups, thereby increasing membrane fluidity. Cholesterol is another well known mediator of membrane fluidity, in turn increasing membrane stiffness. As well, cholesterol is believed to distribute unevenly within lipid membranes leading to the formation of lipid rafts or plaques. In many studies, aspirin has increased positive outcomes for patients with high cholesterol. We are interested if these effects may be, at least partially, the result of a non-specific interaction between aspirin and cholesterol in lipid membranes. We have studied the effect of aspirin on the organization of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) membranes containing cholesterol. Through Langmuir–Blodgett experiments we show that aspirin increases the area per lipid and decreases compressibility at 32.5mol% cholesterol, leading to a significant increase of fluidity of the membranes. Differential scanning calorimetry provides evidence for the formation of meta-stable structures in the presence of aspirin. The molecular organization of lipids, cholesterol and aspirin was studied using neutron diffraction. While the formation of rafts has been reported in binary DPPC/cholesterol membranes, aspirin was found to locally disrupt membrane organization and lead to the frustration of raft formation. Our results suggest that aspirin is able to directly oppose the formation of cholesterol structures through non-specific interactions with lipid membranes. [Display omitted] •Raft forming lipid membranes made of DPPC with 33mol% cholesterol were prepared.•Langmuir trough, DSC, and neutron diffraction experiments were combined.•We observed a non-specific interaction between aspirin and cholesterol in membranes.•Aspirin counteracts cholesterols condensing effect, and re-fluidifies lipid membranes.•We found that aspirin locally disrupts the membrane, thereby inhibiting raft formation.