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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: J Cardiovasc Pharmacol. 2021 Jun 1;77(6):707–717. doi: 10.1097/FJC.0000000000001013

Figure 2: 20-HETE/GPR75 Signaling Pathways.

Figure 2:

The 20-HETE receptor (20HR) (GPR75) is Gαq/11 coupled and promotes changes in intracellular calcium. In endothelial cells, the activation of GPR75 via 20-HETE promotes the transactivation of the epidermal growth factor receptor (EGFR) through a GIT1-/c-SRC-dependent mechanism. Activation of the EGFR results in sequential activation of a MAPK/IƙB/IKK and the translocation of NF-ƙB to stimulate the promoter regions of angiotensin converting enzyme (ACE). Simultaneously, the activation of IKK promotes the recruitment of the chaperone protein HSP90 towards IKK and away from endothelial nitric oxide synthase (eNOS), resulting in the uncoupling of eNOS and a reduction in NO production/bioavailability. Additionally, phospholipase C (PLC) stimulation driven by GPR75 Gαq/11 results in the activation of PKC and subsequent increases in NADPH oxidase-derived reactive oxygen species (ROS) generation. The phosphorylation of the large conductance K channels (BKCa) by PKC also promotes a vasoconstrictor stimuli. These changes promote endothelial dysfunction and set into motion a pro-inflammatory signaling program that elevate various mediators including the synthesis of the chemokine IL-6.