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

Abstract

SummaryAugmented 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 eNOSuncoupling, several senescence markers such as senescence-associated-b-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.

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

“…Compelling evidence implicates that Arg-II plays a dominant role in eNOSuncoupling in human and mouse blood vessels [10,11]. Our recent studies demonstrate that genetic ablation of Arg-II in mice reduces atherosclerosis on the ApoE -/-background, improves glucose homeostasis and insulin sensitivity in mice fed a high fat diet (HFD), which is at least partly attributable to dampening of macrophage inflammatory responses [12].…”

“…The mechanisms of eNOS-uncoupling are multifactorial and have not been fully elucidated [7]. Recent studies including our own demonstrate that the L-arginine ureahydrolase, arginase, including type-I and type-II arginase (Arg-I and Arg-II), is involved in eNOS-uncoupling in vascular diseases [8][9][10].…”

<em>En Face</em> Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries

“…eNOS-uncoupling has been shown to be an important mechanism of endothelial dysfunction under numerous physiological and pathological conditions including aging 22 , atherosclerosis, and obesity 14 . Therefore, here we compare the lean and obese mice to show the representative result of NO and O 2 .− levels in the aortas.…”

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

“…Basal NO production and sensitivity to acetylcholine-mediated vasodilation in thoracic aorta rings were reduced, whereas the pro-inflammatory reaction of ECs was increased in aged mice compared to young mice [172]. In addition, arginase-II (Arg-II) expression/activity was higher in senescent ECs, and Arg-II silencing suppressed eNOSuncoupling and several senescence markers, such as senescence-associated-β-galactosidase activity, p53-S15, p21, and expression of VCAM1 and ICAM1 [173]. Over-expression of Arg-II in non-senescent ECs promoted eNOS-uncoupling and enhanced VCAM1/ICAM1 levels [173].…”

“…In addition, arginase-II (Arg-II) expression/activity was higher in senescent ECs, and Arg-II silencing suppressed eNOSuncoupling and several senescence markers, such as senescence-associated-β-galactosidase activity, p53-S15, p21, and expression of VCAM1 and ICAM1 [173]. Over-expression of Arg-II in non-senescent ECs promoted eNOS-uncoupling and enhanced VCAM1/ICAM1 levels [173].…”