Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39

Abstract

Zn ²⁺ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn ²⁺ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn ²⁺-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn ²⁺ homeostasis takes place, enables extracellular Zn ²⁺ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn ²⁺ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn ²⁺-triggered cellular activity changes, Ca ²⁺ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn ²⁺ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn ²⁺ were not observed in GPR39 ^−/− endothelial cells. Zn ²⁺ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn ²⁺ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream G _αq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.