Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging

Aging Cell. 2012 Dec;11(6):1005-16. doi: 10.1111/acel.12001. Epub 2012 Sep 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Arginase / antagonists & inhibitors
  • Arginase / genetics*
  • Arginase / metabolism
  • Biomarkers / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Female
  • Gene Expression Regulation
  • Gene Silencing
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • RNA, Small Interfering / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism


  • Biomarkers
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Small Interfering
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide Synthase Type III
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • beta-Galactosidase
  • Arg2 protein, mouse
  • Arginase