The Role of TRPM2 in Endothelial Function and Dysfunction

Abstract

The transient receptor potential (TRP) melastatin-like subfamily member 2 (TRPM2) is a non-selective calcium-permeable cation channel. It is expressed by many mammalian tissues, including bone marrow, spleen, lungs, heart, liver, neutrophils, and endothelial cells. The best-known mechanism of TRPM2 activation is related to the binding of ADP-ribose to the nudix-box sequence motif (NUDT9-H) in the C-terminal domain of the channel. In cells, the production of ADP-ribose is a result of increased oxidative stress. In the context of endothelial function, TRPM2-dependent calcium influx seems to be particularly interesting as it participates in the regulation of barrier function, cell death, cell migration, and angiogenesis. Any impairments of these functions may result in endothelial dysfunction observed in such conditions as atherosclerosis or hypertension. Thus, TRPM2 seems to be an attractive therapeutic target for the conditions connected with the increased production of reactive oxygen species. However, before the application of TRPM2 inhibitors will be possible, some issues need to be resolved. The main issues are the lack of specificity, poor membrane permeabilization, and low stability in in vivo conditions. The article aims to summarize the latest findings on a role of TRPM2 in endothelial cells. We also show some future perspectives for the application of TRPM2 inhibitors in cardiovascular system diseases.

Citronellal Attenuates Oxidative Stress–Induced Mitochondrial Damage through TRPM2/NHE1 Pathway and Effectively Inhibits Endothelial Dysfunction in Type 2 Diabetes Mellitus

“…The main mechanism of oxidative stress-induced cell damage is to disrupt intracellular ion homeostasis. TRPM2 is a calcium ion-permeable cation channel that is activated in response to oxidative stress, whereby resulting in the increase in calcium influx in endothelial cells and further causing endothelial dysfunction [ 53 , 54 , 55 ]. Meanwhile, TRPM2 may be involved in high-glucose-induced mitochondrial fission in endothelial cells [ 56 ].…”

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

“…As outlined above, TRPM2 channels are expressed in the lung endothelium and participate in the regulation of barrier function [ 150 , 151 ], cell death, migration and angiogenesis (reviewed in [ 152 ]). Vascular endothelial growth factor (VEGF) in endothelial cells drives their migration, proliferation, and disassembly of adherens junctions, as well as the production of reactive oxygen species (ROS), which activate TRPM2 channels [ 152 ].…”

“…As outlined above, TRPM2 channels are expressed in the lung endothelium and participate in the regulation of barrier function [ 150 , 151 ], cell death, migration and angiogenesis (reviewed in [ 152 ]). Vascular endothelial growth factor (VEGF) in endothelial cells drives their migration, proliferation, and disassembly of adherens junctions, as well as the production of reactive oxygen species (ROS), which activate TRPM2 channels [ 152 ]. Importantly, the deletion of endothelial TRPM2 channels reduce the transendothelial migration of polymorphonuclear neutrophils, which produce ROS in response to LPS from Gram-negative bacterial membranes in the circulating blood of the pulmonary vasculature [ 153 ].…”

Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin

“…Studies have shown that S100 proteins play a role in chemotaxis and activation of immune cells in relationship with OS process and transient receptor potential (TRP). In endothelial cells, specific members of the TRP superfamily of cation channels act as important Ca 2+ influx pathways [ 44 ]. They are involved in endothelium-dependent vasodilation and regulation of permeability and angiogenesis.…”