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34 A critical role for mitochondrial reactive oxygen species in induction of angiotensin II-induced hVSMC senescence
  1. K E Herbert,
  2. Y Mistry
  1. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK


Angiotensin II (Ang II) induces stress-induced premature senescence in human vascular smooth muscle cells (hVSMC) via reactive oxygen species (ROS) generation.1 This effect may explain some of the cardiovascular anti-ageing effects of angiotensin receptor blockers. The current study aimed to investigate the source of ROS mediating this premature senescence. Primary hVSMC were obtained from saphenous veins. Following exposure to Ang II (10–100 nM) with or without inhibitors, superoxide production was measured by lucigenin chemiluminescence and cell senescence by senescence-associated β-galactosidase staining, morphology and growth analysis. Ang II (10 nM) induced a twofold increase in premature senescence in hVSMC. Senescence was blocked by co-incubation with inhibitors of mitochondrial complex I or II (rotenone or TTFA). Therefore, production of ROS by mitochondria was investigated as a possible signalling mechanism. Low concentrations of a mitochondria-targeted antioxidant (mito-TEMPO) completely prevented Ang II- induced senescence, strongly implicating mitochondrial ROS. Moreover, in lysates derived from Ang II-treated cells, addition of rotenone or TTFA suppressed superoxide generation suggesting that a portion of the Ang II derived ROS was due to mitochondrial electron transport. Mitochondrial ROS detected by mitoSOX fluorescence reporter were elevated by Ang II. These data suggest that Ang II induces premature senescence via a mechanism that involves mitochondrial ROS signalling and therefore, add to the evidence for a role of mitochondrial ROS in accelerated cardiovascular cell ageing.

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