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

Published on Jun 1, 2010in British Journal of Pharmacology7.73
· DOI :10.1111/J.1476-5381.2010.00712.X
Mohanraj Rajesh37
Estimated H-index: 37
(NIH: National Institutes of Health),
Partha Mukhopadhyay62
Estimated H-index: 62
(NIH: National Institutes of Health)
+ 3 AuthorsPal Pacher117
Estimated H-index: 117
(NIH: National Institutes of Health)
Sources
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 (CB1) receptor inhibition is beneficial in atherosclerosis and cardiovascular inflammation both in experimental models, as well as in humans. Here, we investigated the effects of CB1 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, CB1 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 CB1 receptors (demonstrated by Western immunoblot and flow cytometry) AEA (5–15 µM) or HU210 (30–1000 nM) triggered concentration- and time-dependent activation of p38 and c-Jun NH2-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 CB1 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 CB1 antagonists, N-acetylcysteine completely prevented these effects. Conclusions and implications:  CB1 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. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x
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