Yepuri, Gautham Velagapudi, Srividya Xiong, Yuyan Rajapakse, Angana G. Montani, Jean-Pierre Ming, Xiu-Fen Yang, Zhihong 2012-09-18 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. application/pdf https://folia.unifr.ch/global/documents/302605 https://folia.unifr.ch/documents/302605/files/yan_pcb.pdf https://folia.unifr.ch/documents/302605/files/yan_pcb_sm.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1111/acel.12001 info:eu-repo/semantics/openAccess License undefined Aging Cell. - 2012, vol. 11, no. 6, p. 1005-1016 Aging Cellular senescence Endothelial cell Inflammation – molecular biology of aging Oxidative stress Signaling info:eu-repo/classification/udc/57 Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging http://purl.org/coar/resource_type/c_6501