Unraveling the Role of Drug-Lipid Interactions in NSAIDs-Induced Cardiotoxicity

Cardiovascular (CV) toxicity is nowadays recognized as a class effect of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). However, their mechanisms of cardiotoxicity are not yet well understood, since different compounds with similar action mechanisms exhibit distinct cardiotoxicity. For instance, diclofenac (DIC) is among the most cardiotoxic compounds, while naproxen (NAP) is associated with low CV risk. In this sense, this study aimed to unravel the role of drug-lipid interactions in NSAIDs-induced cardiotoxicity. For that, DIC and NAP interactions with lipid bilayers as model systems of cell and mitochondrial membranes were characterized by derivative spectrophotometry, fluorometric leakage assays, and synchrotron X-ray scattering. Both DIC and NAP were found to have the ability to permeabilize the membrane models, as well as to alter the bilayers’ structure. The NSAIDs-induced modifications were dependent on the lipid composition of the membrane model, the three-dimensional structure of the drug, as well as the drug:lipid molar ratio tested. Altogether, this work supports the hypothesis that NSAIDs-lipid interactions, in particular at the mitochondrial level, may be another key step among the mechanisms underlying NSAIDs-induced cardiotoxicity.