Membrane Cholesterol Content and Lipid Organization Influence Melittin and Pneumolysin Pore-Forming Activity.

Melittin, the main toxic component in the venom of the European honeybee, interacts with natural and artificial membranes due to its amphiphilic properties. Rather than interacting with a specific receptor, melittin interacts with the lipid components, disrupting the lipid bilayer and inducing ion leakage and osmotic shock. This mechanism of action is shared with pneumolysin and other members of the cholesterol-dependent cytolysin family. In this manuscript, we investigated the inverse correlation for cholesterol dependency of these two toxins. While pneumolysin-induced damage is reduced by pretreatment with the cholesterol-depleting agent methyl-ß-cyclodextrin, the toxicity of melittin, after cholesterol depletion, increased. A similar response was also observed after a short incubation with lipophilic simvastatin, which alters membrane lipid organization and structure, clustering lipid rafts. Therefore, changes in toxin sensitivity can be achieved in cells by depleting cholesterol or changing the lipid bilayer organization.

Pleiotropic effects of statins via interaction with the lipid bilayer: A combined approach.

Statins are effective inhibitors of cholesterol biosynthesis, largely used for prevention of cardiovascular diseases induced by hypercholesterolemia. However, their use in different clinical trials clearly indicate that the general benefits observed with statins are also related to effects beyond the cholesterol lowering. Increasing evidences suggest that some of these cholesterol-independent or "pleiotropic" effects of statins involve the interaction and modification of the membrane bilayers. In this manuscript, using a combined approach based on biophysical (electrochemical impedance spectroscopy on tethered bilayer lipid membranes) and biological methods (hemolysis on erythrocytes and immunocytochemistry on cancer cells), we demonstrate that lipophilic, but not hydrophilic statins are capable of reducing the damage caused by cholesterol-dependent cytolysins. This protection correlates with statins lipophilicity and capacity to interact with the lipid bilayer. Our data suggests lipophilic statins associate with membranes and interfere with the ability of cholesterol dependent cytolysins, to bind to membrane cholesterol. Evaluation of the capacity of statins to modulate cell membrane properties is essential for developing a correct therapeutic approach for cardiovascular diseases as well as for understanding the potential of this class of drugs as adjuvants for drug delivery.