Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy
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,...
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MDPI AG
2020-07-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/7/1703 |
| _version_ | 1827713080231985152 |
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| author | Sabine Böckmann Burkhard Hinz |
| author_facet | Sabine Böckmann Burkhard Hinz |
| author_sort | Sabine Böckmann |
| collection | DOAJ |
| description | 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 (CB<sub>1</sub>, CB<sub>2</sub>, 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 A<sub>1</sub> 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. |
| first_indexed | 2024-03-10T18:27:12Z |
| format | Article |
| id | doaj.art-e4e17729fd644598b738d57b6807cc7c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T18:27:12Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e4e17729fd644598b738d57b6807cc7c2023-11-20T06:56:53ZengMDPI AGCells2073-44092020-07-0197170310.3390/cells9071703Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated AutophagySabine Böckmann0Burkhard Hinz1Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, D-18057 Rostock, GermanyCannabidiol (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 (CB<sub>1</sub>, CB<sub>2</sub>, 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 A<sub>1</sub> 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.https://www.mdpi.com/2073-4409/9/7/1703cannabidiolheme oxygenase-1endothelial cellsapoptosisautophagy |
| spellingShingle | Sabine Böckmann Burkhard Hinz Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy Cells cannabidiol heme oxygenase-1 endothelial cells apoptosis autophagy |
| title | Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy |
| title_full | Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy |
| title_fullStr | Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy |
| title_full_unstemmed | Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy |
| title_short | Cannabidiol Promotes Endothelial Cell Survival by Heme Oxygenase-1-Mediated Autophagy |
| title_sort | cannabidiol promotes endothelial cell survival by heme oxygenase 1 mediated autophagy |
| topic | cannabidiol heme oxygenase-1 endothelial cells apoptosis autophagy |
| url | https://www.mdpi.com/2073-4409/9/7/1703 |
| work_keys_str_mv | AT sabinebockmann cannabidiolpromotesendothelialcellsurvivalbyhemeoxygenase1mediatedautophagy AT burkhardhinz cannabidiolpromotesendothelialcellsurvivalbyhemeoxygenase1mediatedautophagy |