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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:e1.)
© 2003 American Heart Association, Inc.

Vascular Biology

Constitutive Activation of rac1 Results in Mitochondrial Oxidative Stress and Induces Premature Endothelial Cell Senescence

Shailesh S. Deshpande; Bing Qi; Young Chul Park; Kaikobad Irani

From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Kaikobad Irani, Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Ross 1023, 720 Rutland Ave, Baltimore, MD 21205. E-mail: kirani{at}jhmi.edu

Objective— Oxidative stress has been implicated in cellular senescence and vascular aging. We determined the role and mechanism of the small GTPase rac1 in vascular endothelial cell senescence.

Methods and Results— Adenoviral-mediated expression of the constitutively active allele of rac1 (rac1V12) in human umbilical vein endothelial cells resulted in mitochondrial oxidative stress with induction of biochemical, molecular, and morphological features of senescence. Suppression of mitochondrial oxidative stress abrogated rac1-induced premature senescence. Rac1V12 expression also resulted in an increase in endothelial ceramide levels. Moreover, premature endothelial cell senescence induced by an exogenous cell-permeable ceramide analog was not suppressed by inhibiting endogenous rac1 signaling. Finally, in human umbilical vein endothelial cells that had undergone replicative senescence, rac1 was not activated, and expression of the dominant-negative rac1 allele (rac1N17) did not suppress mitochondrial oxidative stress.

Conclusions— These findings paint a picture in which the constitutive activation of rac1, via the generation of ceramide, results in mitochondrial oxidative stress and premature endothelial cell senescence. However, they speak against a role for endogenous rac1 activation in the induction of mitochondrial oxidative stress associated with replicative senescence of endothelial cells.

Key Words: endothelium • rac1 • oxidative stress • senescence • mitochondria

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