Abstract
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been reported to mediate antioxidant, anti-inflammatory, and anti-angiogenic effects in endothelial cells. This study investigated the influence of CBD on the expression of heme oxygenase-1 (HO-1) and its functional role in regulating metabolic, autophagic, and apoptotic processes of human umbilical vein endothelial cells (HUVEC). Concentrations up to 10 µM CBD showed a concentration-dependent increase of HO-1 mRNA and protein and an increase of the HO-1-regulating transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). CBD-induced HO-1 expression was not decreased by antagonists of cannabinoid-activated receptors (CB1, CB2, transient receptor potential vanilloid 1), but by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC). The incubation of HUVEC with 6 µM CBD resulted in increased metabolic activity, while 10 µM CBD caused decreased metabolic activity and an induction of apoptosis, as demonstrated by enhanced caspase-3 cleavage. In addition, CBD triggered a concentration-dependent increase of the autophagy marker LC3A/B-II. Both CBD-induced LC3A/B-II levels and caspase-3 cleavage were reduced by NAC. The inhibition of autophagy by bafilomycin A1 led to apoptosis induction by 6 µM CBD and a further increase of the proapoptotic effect of 10 µM CBD. On the other hand, the inhibition of HO-1 activity with tin protoporphyrin IX (SnPPIX) or knockdown of HO-1 expression by Nrf2 siRNA was associated with a decrease in CBD-mediated autophagy and apoptosis. In summary, our data show for the first time ROS-mediated HO-1 expression in endothelial cells as a mechanism by which CBD mediates protective autophagy, which at higher CBD concentrations, however, can no longer prevent cell death inducing apoptosis.
Highlights
Atherogenesis is the main cause of pathological cardiovascular events such as heart disease and stroke [1]
The inhibition of heme oxygenase-1 (HO-1) activity with tin protoporphyrin IX (SnPPIX) or knockdown of HO-1 expression by nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA was associated with a decrease in CBD-mediated autophagy and apoptosis
In the search for a possible target for CBD in the prevention of endothelial cell death, we have focused on the enzyme HO-1
Summary
Atherogenesis is the main cause of pathological cardiovascular events such as heart disease and stroke [1]. Within this multifactorial process, endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis have been identified as mechanisms involved in the formation of atherosclerotic plaques [2]. The available antioxidant defense systems [3,4]. One of several promising targets against the progression of inflammatory vascular diseases including atherosclerosis represents the inhibition of endothelial cell apoptosis [5,6,7]. Anti-inflammatory, and cytoprotective enzyme is heme oxygenase-1
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