Cannabis sativa extracts inhibit LDL oxidation and the formation of foam cells in vitro, acting as potential multi-step inhibitors of atherosclerosis development

Atherosclerotic disease is the leading cause of death world-wide. Our goal was to explore the effect of phytocannabinoids on the molecular mechanisms triggering the development of the atheromatous lesion. Three cannabis sativa extracts of different chemotypes were chemically characterized by UPLC-DAD. The capacity of the extracts to prevent the oxidation of LDL, the formation of foam cells and the activation of an inflammatory response by J774 cells, were monitored by UV-Vis spectrometry, confocal-microscopy and western blot. Three varieties of cannabis sativa, with high (E1), intermediate (E2) and low (E3) THC/CBD ratios were selected. The three cannabis extracts inhibited the oxidation of LDL by copper ions and the formation of foam cells by J774.1 cells challenged with oxLDL (ED50 5-12 μg mL-1). The effect of the cannabinoid extracts on the endocytic process was independent of the canonical cannabinoid receptors, CB1 and CB2, but related to the action of non-canonical receptors (TRPV1, TRPV4 and GPR55), involved in calcium signaling. Decreased levels of CD36 and OLR1 scavenger receptors were, at least partially, responsible for the diminished uptake of oxLDL induced by phytocannabinoids. The downregulation of CD36 and OLR1 could be explained by the observed inhibitory effect of the cannabis extracts on the activation of the NFκB pathway by oxLDL. Phytocannabinoids interfere with the main events leading to the development of the atheromatous plaque, opening new venues on atherosclerosis therapy.