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

Abstract

Abstract-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 ␤-galactosidase staining. Exposure to Ang II increased DNA damage in hVSMCs within 4 hours. Inhibition by an AT 1 receptor antagonist (losartan metabolite: E3174) or catalase, confirmed that Ang II-induced DNA damage was AT 1 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 Ͼ2-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.

Bradykinin Protects Against Oxidative Stress–Induced Endothelial Cell Senescence

“…Although we are not aware of any other study showing a similar role of G protein-coupled receptors, the contrary effect, ie, induction of senescence, can result from stimulation of angiotensin II type 1 receptors in vascular smooth muscle cells 24 and endothelial progenitor cells. 25 Therefore, these previous studies, combined with our present results, suggest that intervention through RAS inhibition can be dually protective: on the one hand, angiotensin II type 1 receptor blockade prevents ROS-induced senescence, and on the other hand, ACE inhibition protects against ROS-induced senescence through stimulation of BK B2 receptor signaling.…”

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

“…The serum Gas6 level decreases with age and are positively correlated with testosterone level (Hung et al 2010). In this study, we established the model of VSMC senescence induced by angiotensin II, for chronic inflammation mediated by angiotensin II was considered to play a pivotal role in age-related vascular remodeling and cellular senescence (Herbert et al 2008;Kunieda et al 2006;Nguyen Dinh Cat et al 2013;Wang et al 2014). The p16 INK4a and p21 Cip1 protein expression levels and SA-β-Gal staining rate were used to evaluate the degree of cellular senescence (Campisi 2005;Goberdhan et al 1995).…”

Aging and the Renin-Angiotensin System

“…At variance, uncontrolled Ang IIdependent ROS generation takes place as a consequence of age-associated activation of RAS (Figure 2). 32,33 Ang II also accelerates cellular senescence by inducing the shortening of telomeres and cell cycle arrest, effects that are reversed by losartan. 34 Age-dependent stimulation of local RAS in the myocardium induces NADPH oxidase activity and drives cardiac hypertrophy and fibrosis, features that could be replicated in young rats chronically infused with Ang II.…”