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Rac1 inhibits TNF‐α‐induced endothelial cell apoptosis: dual regulation by reactive oxygen species

Reactive oxygen species (ROS) have been implicated as mediators of tumor necrosis factor‐alpha (TNF) ‐induced apoptosis. In addition to leading to cell death, ROS can also promote cell growth and/or survival. We investigated these two roles of ROS in TNF‐induced endothelial cell apoptosis. Human umbilical vein endothelial cells (HUVECs) stimulated with TNF produced an intracellular burst of ROS. Adenoviral‐mediated gene transfer of a dominant negative form of the small GTPase Rac1 (Rac1N17) partially suppressed the TNF‐induced oxidative burst without affecting TNF‐induced mitochondrial ROS production. HUVECs were protected from TNF‐induced apoptosis. Expression of Rac1N17 blocked TNF‐induced activation of nuclear factor‐kappa B (NF‐κB), increased activity of caspase‐3, and markedly augmented endothelial cell susceptibility to TNF‐induced apoptosis. Direct inhibition of NF‐κB through adenoviral expression of the super repressor form of inhibitor of kBα (I‐κB S32/36A) also increased susceptibility of HUVECs to TNF‐induced apoptosis. Rotenone, a mitochondrial electron transport chain inhibitor, suppressed TNF‐induced mitochondrial ROS production, proteolytic cleavage of procaspase‐3, and apoptosis. These findings show that Rac1 is an important regulator of TNF‐induced ROS production in endothelial cells. Moreover, they suggest that Rac1‐dependent ROS, directly or indirecly, lead to protection against TNF‐induced death, whereas mitochondrial‐derived ROS promote TNF‐induced apoptosis.—Deshpande, S. S., Angkeow, P., Huang, J., Ozaki, M., Irani, K. Rac1 inhibits TNF‐α‐induced endothelial cell apoptosis: dual regulation by reactive oxygen species. FASEB J. 14, 1705–1714 (2000)