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(Circulation Research. 2008;102:347.)
© 2008 American Heart Association, Inc.

Cellular Biology

Role of TRPM2 Channel in Mediating H₂O₂-Induced Ca²⁺ Entry and Endothelial Hyperpermeability

Claudie M. Hecquet, Gias U. Ahmmed, Stephen M. Vogel, Asrar B. Malik

From the Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago.

Correspondence to Asrar B. Malik, Department of Pharmacology, University of Illinois at Chicago, College of Medicine, 835 South Wolcott Ave (M/C 868), Chicago, IL 60612. E-mail abmalik{at}uic.edu

Oxidative stress through the production of oxygen metabolites such as hydrogen peroxide (H₂O₂) increases vascular endothelial permeability. H₂O₂ 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 Ca²⁺-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 H₂O₂ induced a cationic current measured by patch-clamp recording and Ca²⁺ entry detected by intracellular fura-2 fluorescence. H₂O₂ in a concentration-dependent manner also decreased trans-monolayer transendothelial electrical resistance for 3 hours (with maximal effect seen at 300 µmol/L H₂O₂), indicating opening of interendothelial junctions. The cationic current, Ca²⁺ entry, and transendothelial electrical resistance decrease elicited by H₂O₂ were inhibited by siRNA depleting TRPM2 or antibody blocking of TRPM2. H₂O₂ 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 H₂O₂-mediated Ca²⁺ entry, cationic current, and the transendothelial electrical resistance decrease. Thus, TRPM2 mediates H₂O₂-induced increase in endothelial permeability through the activation of Ca²⁺ entry via TRPM2. TRPM2 represents a novel therapeutic target directed against oxidant-induced endothelial barrier disruption.

Key Words: transient receptor potential channels • Ca²⁺ influx • endothelial vascular barrier • permeability • lung injury

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Another TRP to Endothelial Dysfunction: TRPM2 and Endothelial Permeability

Alexander Dietrich and Thomas Gudermann
Circ. Res. 2008 102: 275-277. [Full Text] [PDF]

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