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Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells.
Br J Pharmacol. 2010 Jun; 160(3):688-700.BJ

Abstract

BACKGROUND AND PURPOSE

Impaired endothelial activity and/or cell death play a critical role in the development of vascular dysfunction associated with congestive heart failure, diabetic complications, hypertension, coronary artery disease and atherosclerosis. Increasing evidence suggests that cannabinoid 1 (CB(1)) receptor inhibition is beneficial in atherosclerosis and cardiovascular inflammation both in experimental models, as well as in humans. Here, we investigated the effects of CB(1) receptor activation with the endocannabinoid anandamide (AEA) or synthetic agonist HU210 on cell death and interrelated signal transduction pathways in human primary coronary artery endothelial cells (HCAECs).

EXPERIMENTAL APPROACH

Cell death, CB(1) receptor expression, reactive oxygen species (ROS) generation and activation of signal transduction pathways in HCAECs were determined by flow cytometry and molecular biology tools.

KEY RESULTS

In HCAECs expressing CB(1) receptors (demonstrated by Western immunoblot and flow cytometry) AEA (5-15 microM) or HU210 (30-1000 nM) triggered concentration- and time-dependent activation of p38 and c-Jun NH(2)-terminal protein kinase (JNK)-mitogen-activated protein kinases (MAPKs), cell death and ROS generation. The AEA- or HU210-induced cell death and MAPK activation were attenuated by CB(1) antagonists [SR141716 (rimonabant) and AM281], inhibitors of p38 and JNK-MAPKs or the antioxidant N-acetylcysteine. N-acetylcysteine alone prevented AEA- or HU210-induced ROS generation, but only partially attenuated MAPK activation and cell death. In contrast, in combination with CB(1) antagonists, N-acetylcysteine completely prevented these effects.

CONCLUSIONS AND IMPLICATIONS

CB(1) receptor activation in endothelial cells may amplify the ROS-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, thereby contributing to the development of endothelial dysfunction and pathophysiology of multiple cardiovascular diseases.

Authors+Show Affiliations

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

20590572

Citation

Rajesh, Mohanraj, et al. "Cannabinoid-1 Receptor Activation Induces Reactive Oxygen Species-dependent and -independent Mitogen-activated Protein Kinase Activation and Cell Death in Human Coronary Artery Endothelial Cells." British Journal of Pharmacology, vol. 160, no. 3, 2010, pp. 688-700.
Rajesh M, Mukhopadhyay P, Haskó G, et al. Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol. 2010;160(3):688-700.
Rajesh, M., Mukhopadhyay, P., Haskó, G., Liaudet, L., Mackie, K., & Pacher, P. (2010). Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. British Journal of Pharmacology, 160(3), 688-700. https://doi.org/10.1111/j.1476-5381.2010.00712.x
Rajesh M, et al. Cannabinoid-1 Receptor Activation Induces Reactive Oxygen Species-dependent and -independent Mitogen-activated Protein Kinase Activation and Cell Death in Human Coronary Artery Endothelial Cells. Br J Pharmacol. 2010;160(3):688-700. PubMed PMID: 20590572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. AU - Rajesh,Mohanraj, AU - Mukhopadhyay,Partha, AU - Haskó,György, AU - Liaudet,Lucas, AU - Mackie,Ken, AU - Pacher,Pál, PY - 2010/7/2/entrez PY - 2010/7/2/pubmed PY - 2010/10/15/medline SP - 688 EP - 700 JF - British journal of pharmacology JO - Br J Pharmacol VL - 160 IS - 3 N2 - BACKGROUND AND PURPOSE: Impaired endothelial activity and/or cell death play a critical role in the development of vascular dysfunction associated with congestive heart failure, diabetic complications, hypertension, coronary artery disease and atherosclerosis. Increasing evidence suggests that cannabinoid 1 (CB(1)) receptor inhibition is beneficial in atherosclerosis and cardiovascular inflammation both in experimental models, as well as in humans. Here, we investigated the effects of CB(1) receptor activation with the endocannabinoid anandamide (AEA) or synthetic agonist HU210 on cell death and interrelated signal transduction pathways in human primary coronary artery endothelial cells (HCAECs). EXPERIMENTAL APPROACH: Cell death, CB(1) receptor expression, reactive oxygen species (ROS) generation and activation of signal transduction pathways in HCAECs were determined by flow cytometry and molecular biology tools. KEY RESULTS: In HCAECs expressing CB(1) receptors (demonstrated by Western immunoblot and flow cytometry) AEA (5-15 microM) or HU210 (30-1000 nM) triggered concentration- and time-dependent activation of p38 and c-Jun NH(2)-terminal protein kinase (JNK)-mitogen-activated protein kinases (MAPKs), cell death and ROS generation. The AEA- or HU210-induced cell death and MAPK activation were attenuated by CB(1) antagonists [SR141716 (rimonabant) and AM281], inhibitors of p38 and JNK-MAPKs or the antioxidant N-acetylcysteine. N-acetylcysteine alone prevented AEA- or HU210-induced ROS generation, but only partially attenuated MAPK activation and cell death. In contrast, in combination with CB(1) antagonists, N-acetylcysteine completely prevented these effects. CONCLUSIONS AND IMPLICATIONS: CB(1) receptor activation in endothelial cells may amplify the ROS-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, thereby contributing to the development of endothelial dysfunction and pathophysiology of multiple cardiovascular diseases. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/20590572/Cannabinoid_1_receptor_activation_induces_reactive_oxygen_species_dependent_and__independent_mitogen_activated_protein_kinase_activation_and_cell_death_in_human_coronary_artery_endothelial_cells_ L2 - https://doi.org/10.1111/j.1476-5381.2010.00712.x DB - PRIME DP - Unbound Medicine ER -