CB1 RECEPTOR ACTIVATION INDUCES ROS‐DEPENDENT AND INDEPENDENT MAPK ACTIVATION AND CELL DEATH IN HUMAN ENDOTHELIAL CELLS AND CARDIOMYOCYTES

Here, we have 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) and cardiomyocytes (HCMs). Cell death, CB1 receptor expression, reactive oxygen species (ROS) generation, and activation of signal transduction pathways in cells were determined by flow cytometry and molecular biology tools. In HCAECs or HCM expressing CB1 receptors AEA or HU210 triggered concentration‐ and time‐dependent activation of p38 and JNK MAPKs, cell death, and ROS generation. The AEA or HU210‐induced cell death and MAPK activation were attenuated by CB1 antagonists (SR141716 and AM281), inhibitors of p38 and JNK MAPKs or the antioxidant NAC. NAC alone prevented AEA‐ or HU210‐induced ROS generation, but only partially attenuated MAPK activation and cell death. In contrast, in combination with CB1 antagonists NAC completely prevented these effects. Collectively, CB1 receptor activation in endothelial cells and cardiomyocytes contributes to the ROS‐MAPK‐cell death pathways in pathological conditions were the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrative stress, thereby contributing to the development of endothelial dysfunction and pathophysiology of multiple cardiovascular diseases. This study was supported by intramural funds from NIH/NIAAA.