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(Circulation Research. 2008;102:201.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Angiotensin II–Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways

Karl E. Herbert^*, Yogita Mistry^*, Richard Hastings, Toryn Poolman, Laura Niklason, Bryan Williams

From the Department of Cardiovascular Sciences (K.E.H., Y.M., R.H., T.P., B.W.), University of Leicester, UK; and Biomedical Engineering (L.N.), Yale University, New Haven, Conn.

Correspondence to Prof Bryan Williams, MD, FRCP, FAHA, Department of Cardiovascular Sciences, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK. E-mail bw17{at}le.ac.uk

Angiotensin II (Ang II) induces reactive oxygen species (ROS) production by human vascular smooth muscle cells (hVSMCs). ROS have been implicated in the development of both acute stress-induced premature senescence (SIPS) and chronic replicative senescence. Global oxidative DNA damage triggers SIPS and telomere DNA damage accelerates replicative senescence, both mediated via p53. This study tests the hypothesis that DNA is an important target for Ang II–induced ROS leading to senescence via telomere-dependent and independent pathways. DNA damage was quantified using the Comet assay, telomere DNA length by Southern blotting and hVSMC senescence by senescence-associated β-galactosidase staining. Exposure to Ang II increased DNA damage in hVSMCs within 4 hours. Inhibition by an AT₁ receptor antagonist (losartan metabolite: E3174) or catalase, confirmed that Ang II–induced DNA damage was AT₁ receptor-mediated, via the induction of ROS. Acute exposure to Ang II resulted in SIPS within 24 hours that was prevented by coincubation with E3174 or catalase. SIPS was associated with increased p53 expression but was not dependent on telomere attrition because overexpression of human telomerase did not prevent Ang II–induced SIPS. Exposure to Ang II over several population doublings accelerated the rate of telomere attrition (by >2-fold) and induced premature replicative senescence of hVSMCs—an effect that was also attenuated by E3174 or catalase. These data demonstrate that Ang II–induced ROS-mediated DNA damage results in accelerated biological aging of hVSMCs via 2 mechanisms: (1) Acute SIPS, which is telomere independent, and (2) accelerated replicative senescence which is associated with accelerated telomere attrition.

Key Words: vascular smooth muscle cell • senescence • angiotensin II • reactive oxygen species • DNA damage

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