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

Abstract

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.

• Authors: Gautham Yepuri, Srividya Velagapudi, Yuyan Xiong, Angana G Rajapakse, Jean-Pierre Montani, Xiu-Fen Ming, Zhihong Yang
• Journal: Aging cell (Aging Cell) Vol. 11 Issue 6 Pg. 1005-16 (Dec 2012) ISSN: 1474-9726 [Electronic] England
• PMID: 22928666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Chemical References

• 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

Topics

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