Statin Action Targets Lipid Rafts of Cell Membranes: GIXD/PM-IRRAS Investigation of Langmuir Monolayers

Lipid rafts are condensedregions of cell membranes richin cholesteroland sphingomyelin, which constitute the target for anticholesterolemicdrugs - statins. In this work, we use for the first time a combinedgrazing-incidence X-ray diffraction (GIXD)/polarization modulationinfrared reflection absorption spectroscopy (PM-IRRAS)/Brewster anglemicroscopy (BAM) approach to show the statin effect on model lipidrafts and its components assembled in Langmuir monolayers at the air-waterinterface. Two representatives of these drugs, fluvastatin (FLU) andcerivastatin (CER), of different hydrophobicity were chosen, whilecholesterol (Chol) and sphingomyelin (SM), and their 1:1 mixture wereselected to form condensed monolayers of lipid rafts. The effect ofstatins on the single components of lipid rafts indicated that boththe hydrophobicity of the drugs and the organization of the layerdetermined the drug-lipid interaction. For cholesterol monolayers,only the most hydrophobic CER was effectively changing the film structure,while for the less organized sphingomyelin, the biggest effect wasobserved for FLU. This drug affected both the polar headgroup regionas shown by PM-IRRAS results and the 2D crystalline structure of theSM monolayer as evidenced by GIXD. Measurements performed for Chol/SM1:1 models proved also that the statin effect depends on the presenceof Chol-SM complexes. In this case, the less hydrophobic FLUwas not able to penetrate the binary layer at all, while exposureto the hydrophobic CER resulted in the phase separation and formationof ordered assemblies. The changes in the membrane properties werevisualized by BAM images and GIXD patterns and confirmed by thermodynamicparameters of hysteresis in the Langmuir monolayer compression-decompressionexperiments.