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

doi:10.1161/01.ATV.0000047869.13737.53

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Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence

Journal article

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Peer reviewed

Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence

Shailesh S Deshpande, Bing Qi, Young Chul Park and Kaikobad Irani

Arteriosclerosis, thrombosis, and vascular biology, Vol.23(1), pp.e1-6

01/01/2003

DOI: 10.1161/01.ATV.0000047869.13737.53

PMID: 12524240

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Abstract

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. 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. 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.

Cell Line

Reactive Oxygen Species - metabolism

Humans

Oxidative Stress - physiology

Cellular Senescence - physiology

Mitochondria - metabolism

Aging, Premature - pathology

rac1 GTP-Binding Protein - physiology

Endothelium, Vascular - metabolism

Endothelium, Vascular - pathology

Umbilical Veins - pathology

Mitochondria - chemistry

Aging, Premature - metabolism

rac1 GTP-Binding Protein - metabolism

Umbilical Veins - metabolism

Details

Title: Subtitle: Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence
Creators: Shailesh S Deshpande - Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA
Bing Qi
Young Chul Park
Kaikobad Irani
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.23(1), pp.e1-6
Publisher: United States
DOI: 10.1161/01.ATV.0000047869.13737.53
PMID: 12524240
ISSN: 1079-5642
eISSN: 1524-4636
Language: English
Date published: 01/01/2003
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047663202771

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