Equally contributing authors.
Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging
Article first published online: 18 SEP 2012
© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland
Volume 11, Issue 6, pages 1005–1016, December 2012
How to Cite
Yepuri, G., Velagapudi, S., Xiong, Y., Rajapakse, A. G., Montani, J.-P., Ming, X.-F. and Yang, Z. (2012), Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. Aging Cell, 11: 1005–1016. doi: 10.1111/acel.12001
- Issue published online: 15 NOV 2012
- Article first published online: 18 SEP 2012
- Accepted manuscript online: 29 AUG 2012 06:17AM EST
- Accepted for publication 20 August 2012
- cellular senescence;
- endothelial cell;
- inflammation – molecular biology of aging;
- oxidative stress;
Augmented activities of both arginase and S6K1 are involved in endothelial dysfunction in aging. This study was to investigate whether or not there is a crosstalk between arginase and S6K1 in endothelial inflammation and aging in senescent human umbilical vein endothelial cells and in aging mouse models. We show increased arginase-II (Arg-II) expression/activity in senescent endothelial cells. Silencing Arg-II in senescent cells suppresses eNOS-uncoupling, several senescence markers such as senescence-associated-β-galactosidase activity, p53-S15, p21, and expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1). Conversely, overexpressing Arg-II in nonsenescent cells promotes eNOS-uncoupling, endothelial senescence, and enhances VCAM1/ICAM1 levels and monocyte adhesion, which are inhibited by co-expressing superoxide dismutase-1. Moreover, overexpressing S6K1 in nonsenescent cells increases, whereas silencing S6K1 in senescent cells decreases Arg-II gene expression/activity through regulation of Arg-II mRNA stability. Furthermore, S6K1 overexpression exerts the same effects as Arg-II on endothelial senescence and inflammation responses, which are prevented by silencing Arg-II, demonstrating a role of Arg-II as the mediator of S6K1-induced endothelial aging. Interestingly, mice that are deficient in Arg-II gene (Arg-II−/−) are not only protected from age-associated increase in Arg-II, VCAM1/ICAM1, aging markers, and eNOS-uncoupling in the aortas but also reveal a decrease in S6K1 activity. Similarly, silencing Arg-II in senescent cells decreases S6K1 activity, demonstrating that Arg-II also stimulates S6K1 in aging. Our study reveals a novel mechanism of mutual positive regulation between S6K1 and Arg-II in endothelial inflammation and aging. Targeting S6K1 and/or Arg-II may decelerate vascular aging and age-associated cardiovascular disease development.