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Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy.
Cells. 2020 07 16; 9(7)C

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.

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Authors+Show Affiliations

Böckmann S
Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, Germany.
Hinz B
Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, Germany.

MeSH

ApoptosisAutophagyCannabidiolCell SurvivalHeme Oxygenase-1Human Umbilical Vein Endothelial CellsHumansModels, BiologicalNF-E2-Related Factor 2ProtoporphyrinsRNA, Small InterferingReactive Oxygen SpeciesTime Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32708634

Citation

Böckmann, Sabine, and Burkhard Hinz. "Cannabidiol Promotes Endothelial Cell Survival By Heme Oxygenase-1-Mediated Autophagy." Cells, vol. 9, no. 7, 2020.
Böckmann S, Hinz B. Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. Cells. 2020;9(7).
Böckmann, S., & Hinz, B. (2020). Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. Cells, 9(7). https://doi.org/10.3390/cells9071703
Böckmann S, Hinz B. Cannabidiol Promotes Endothelial Cell Survival By Heme Oxygenase-1-Mediated Autophagy. Cells. 2020 07 16;9(7) PubMed PMID: 32708634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy. AU - Böckmann,Sabine, AU - Hinz,Burkhard, Y1 - 2020/07/16/ PY - 2020/05/19/received PY - 2020/07/06/revised PY - 2020/07/10/accepted PY - 2020/7/26/entrez PY - 2020/7/28/pubmed PY - 2021/3/6/medline KW - apoptosis KW - autophagy KW - cannabidiol KW - endothelial cells KW - heme oxygenase-1 JF - Cells JO - Cells VL - 9 IS - 7 N2 - 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. SN - 2073-4409 UR - https://www.unboundmedicine.com/medline/citation/32708634/Cannabidiol_Promotes_Endothelial_Cell_Survival_by_Heme_Oxygenase_1_Mediated_Autophagy_ DB - PRIME DP - Unbound Medicine ER -