Affiliation:
1. From the Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago.
Abstract
Oxidative stress through the production of oxygen metabolites such as hydrogen peroxide (H
2
O
2
) increases vascular endothelial permeability. H
2
O
2
stimulates ADP-ribose formation, which in turn opens transient receptor potential melastatin (TRPM)2 channels. Here, in endothelial cells, we demonstrate transcript and protein expression of TRPM2, a Ca
2+
-permeable, nonselective cation channel. We further show the importance of TRPM2 expression in signaling of increased endothelial permeability by oxidative stress. Exposure of endothelial cell monolayers to sublytic concentrations of H
2
O
2
induced a cationic current measured by patch-clamp recording and Ca
2+
entry detected by intracellular fura-2 fluorescence. H
2
O
2
in a concentration-dependent manner also decreased trans-monolayer transendothelial electrical resistance for 3 hours (with maximal effect seen at 300 μmol/L H
2
O
2
), indicating opening of interendothelial junctions. The cationic current, Ca
2+
entry, and transendothelial electrical resistance decrease elicited by H
2
O
2
were inhibited by siRNA depleting TRPM2 or antibody blocking of TRPM2. H
2
O
2
responses were attenuated by overexpression of the dominant-negative splice variant of TRPM2 or inhibition of ADP-ribose formation. Overexpression of the full-length TRPM2 enhanced H
2
O
2
-mediated Ca
2+
entry, cationic current, and the transendothelial electrical resistance decrease. Thus, TRPM2 mediates H
2
O
2
-induced increase in endothelial permeability through the activation of Ca
2+
entry via TRPM2. TRPM2 represents a novel therapeutic target directed against oxidant-induced endothelial barrier disruption.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
200 articles.
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