Low-density lipoproteins investigated under high hydrostatic pressure by elastic incoherent neutron scattering

International audienceHuman low-density lipoprotein (LDL) is a highly complex nano-particle built up of various lipid classes and a single large protein moiety (apoB-100) owning essential physiological functions in the human body. Besides its vital role as a supplier of cholesterol and fat for peripheral tissues and cells, it is also a known key player in the formation of atherosclerosis. Due to these important roles in physiology and pathology the elucidation of structural and dynamical details is of great interest. In the current study we drew a broader picture of LDL dynamics using elastic incoherent neutron scattering (EINS) as a function of specified temperature and pressure points. We not only investigated a normolipidemic LDL sample, but also a triglyceride-rich and an oxidized one to mimic pathologic conditions as found under hyperlipidemic conditions or in atherosclerotic plaques, respectively. We could show that pressure has a significant effect on atomic motions in modified forms of LDL, whereas the normolipidemic sample seems to cope much better with high-pressure conditions irrespective of temperature. These findings might be explained by the altered lipid composition, which is either caused through elevated triglyceride content or modifications through lipid peroxidation

High hydrostatic pressure specifically affects molecular dynamics and shape of low-density lipoprotein particles

International audienceLipid composition of human low-density lipoprotein (LDL) and its physicochemical characteristics are relevant for proper functioning of lipid transport in the blood circulation. To explore dynamical and structural features of LDL particles with either a normal or a triglyceride-rich lipid composition we combined coherent and incoherent neutron scattering methods. The investigations were carried out under high hydrostatic pressure (HHP), which is a versatile tool to study the physicochemical behavior of biomolecules in solution at a molecular level. Within both neutron techniques we applied HHP to probe the shape and degree of freedom of the possible motions (within the time windows of 15 and 100 ps) and consequently the flexibility of LDL particles. We found that HHP does not change the types of motion in LDL, but influences the portion of motions participating. Contrary to our assumption that lipoprotein particles, like membranes, are highly sensitive to pressure we determined that LDL copes surprisingly well with high pressure conditions, although the lipid composition, particularly the triglyceride content of the particles, impacts the molecular dynamics and shape arrangement of LDL under pressure

Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries

Pritesh P Jain,1 Regina Leber,1,2 Chandran Nagaraj,1 Gerd Leitinger,3 Bernhard Lehofer,4 Horst Olschewski,1,5 Andrea Olschewski,1,6 Ruth Prassl,1,4 Leigh M Marsh11Ludwig Boltzmann Institute for Lung Vascular Research, 2Biophysics Division, Institute of Molecular Biosciences, University of Graz, 3Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology, and Embryology, 4Institute of Biophysics, 5Division of Pulmonology, Department of Internal Medicine, 6Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, AustriaAbstract: Prostacyclin analogues are standard therapeutic options for vasoconstrictive diseases, including pulmonary hypertension and Raynaud’s phenomenon. Although effective, these treatment strategies are expensive and have several side effects. To improve drug efficiency, we tested liposomal nanoparticles as carrier systems. In this study, we synthesized liposomal nanoparticles tailored for the prostacyclin analogue iloprost and evaluated their pharmacologic efficacy on mouse intrapulmonary arteries, using a wire myograph. The use of cationic lipids, stearylamine, or 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) in liposomes promoted iloprost encapsulation to at least 50%. The addition of cholesterol modestly reduced iloprost encapsulation. The liposomal nanoparticle formulations were tested for toxicity and pharmacologic efficacy in vivo and ex vivo, respectively. The liposomes did not affect the viability of human pulmonary artery smooth muscle cells. Compared with an equivalent concentration of free iloprost, four out of the six polymer-coated liposomal formulations exhibited significantly enhanced vasodilation of mouse pulmonary arteries. Iloprost that was encapsulated in liposomes containing the polymer polyethylene glycol exhibited concentration-dependent relaxation of arteries. Strikingly, half the concentration of iloprost in liposomes elicited similar pharmacologic efficacy as nonencapsulated iloprost. Cationic liposomes can encapsulate iloprost with high efficacy and can serve as potential iloprost carriers to improve its therapeutic efficacy.Keywords: prostacyclin, cationic liposomes, pulmonary hypertension, wire myograp