| 25635535 | Previous work showed that augmented arginase-II (Arg-II) and S6K1 interact with each other to promote endothelial senescence through uncoupling of endothelial nitric oxide synthase (eNOS) |
| 25635535 | Silencing Arg-II or p38alpha in senescent cells recouples eNOS and inhibits IL-6 and IL-8 secretion |
| 25635535 | Silencing Arg-II or p38a or S6K1 inhibits each other in senescence endothelial cells |
| 25484082 | ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis |
| 25484082 | Impaired autophagy function and enhanced ARG2 (arginase 2)-MTOR (mechanistic target of rapamycin) crosstalk are implicated in vascular aging and atherosclerosis |
| 25484082 | We are interested in the role of ARG2 and the potential underlying mechanism(s) in modulation of endothelial autophagy |
| 25484082 | Using human nonsenescent "young" and replicative senescent endothelial cells as well as Apolipoprotein E-deficient (apoe(-/-)Arg2(+/+)) and Arg2-deficient apoe(-/-) (apoe(-/-)arg2(-/-)) mice fed a high-fat diet for 10 wk as the atherosclerotic animal model, we show here that overexpression of ARG2 in the young cells suppresses endothelial autophagy with concomitant enhanced expression of RICTOR, the essential component of the MTORC2 complex, leading to activation of the AKT-MTORC1-RPS6KB1/S6K1 (ribosomal protein S6 kinase, 70kDa, polypeptide 1) cascade and inhibition of PRKAA/AMPK (protein kinase, AMP-activated, alpha catalytic subunit) |
| 25484082 | Expression of an inactive ARG2 mutant (H160F) had the same effect |
| 25484082 | Moreover, silencing RPS6KB1 or expression of a constitutively active PRKAA prevented autophagy suppression by ARG2 or H160F |
| 25484082 | In senescent cells, enhanced ARG2-RICTOR-AKT-MTORC1-RPS6KB1 and decreased PRKAA signaling and autophagy were observed, which was reversed by silencing ARG2 but not by arginase inhibitors |
| 25484082 | In line with the above observations, genetic ablation of Arg2 in apoe(-/-) mice reduced RPS6KB1, enhanced PRKAA signaling and endothelial autophagy in aortas, which was associated with reduced atherosclerosis lesion formation |
| 25484082 | Taken together, the results demonstrate that ARG2 impairs endothelial autophagy independently of the L-arginine ureahydrolase activity through activation of RPS6KB1 and inhibition of PRKAA, which is implicated in atherogenesis |
| 24860943 | Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling |
| 24860943 | While acute L-arginine treatment enhances endothelial NO production accompanied with superoxide production and activation of S6K1 but no up-regulation of arginase-II, chronic L-arginine supplementation causes endothelial senescence, up-regulation of the adhesion molecule expression, and eNOS-uncoupling (decreased NO and enhanced superoxide production), which are associated with S6K1 activation and up-regulation of arginase-II |
| 24860943 | Silencing either S6K1 or arginase-II inhibits up-regulation/activation of each other, prevents endothelial dysfunction, adhesion molecule expression, and senescence under the chronic L-arginine supplementation condition |
| 24860943 | These results demonstrate that S6K1 and arginase-II form a positive circuit mediating the detrimental effects of chronic L-arginine supplementation on endothelial cells |
| 23832324 | Arginase-II (Arg-II) has been shown to promote vascular dysfunction and plaque vulnerability phenotypes in mice through uncoupling of endothelial nitric oxide synthase and activation of macrophage inflammation |
| 23832324 | The function of Arg-II in VSMCs with respect to plaque vulnerability is unknown |
| 23832324 | This study investigated the functions of Arg-II in VSMCs linking to plaque vulnerability |
| 23832324 | In nonsenescent VSMCs, overexpressing wild-type Arg-II or an l-arginine ureahydrolase inactive Arg-II mutant (H160F) caused similar effects on mitochondrial dysfunction, cell apoptosis, and senescence, which were abrogated by silencing p66Shc or p53 |
| 23832324 | The activation of p66Shc but not p53 by Arg-II was dependent on extracellular signal-regulated kinases (ERKs) and sequential activation of 40S ribosomal protein S6 kinase 1 (S6K1)-c-Jun N-terminal kinases (JNKs) |
| 23832324 | In senescent VSMCs, Arg-II and S6K1, ERK-p66Shc, and p53 signaling levels were increased |
| 23832324 | Silencing Arg-II reduced all these signalings and cell senescence/apoptosis |
| 23832324 | Conversely, silencing p66Shc reduced ERK and S6K1 signaling and Arg-II levels and cell senescence/apoptosis |
| 23832324 | Furthermore, genetic ablation of Arg-II in ApoE(-/-) mice reduced the aforementioned signaling and apoptotic VSMCs in the plaque of aortic roots |
| 23832324 | CONCLUSIONS: Arg-II, independently of its l-arginine ureahydrolase activity, promotes mitochondrial dysfunction leading to VSMC senescence/apoptosis through complex positive crosstalk among S6K1-JNK, ERK, p66Shc, and p53, contributing to atherosclerotic vulnerability phenotypes in mice |
| 22928666 | Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging |
| 22928666 | We show increased arginase-II (Arg-II) expression/activity in senescent endothelial cells |
| 22928666 | Silencing Arg-II in senescent cells suppresses eNOS-uncoupling, several senescence markers such as senescence-associated-beta-galactosidase activity, p53-S15, p21, and expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) |
| 22928666 | 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 |
| 22928666 | 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 |
| 22928666 | 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 |
| 22928666 | 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 |
| 22928666 | Similarly, silencing Arg-II in senescent cells decreases S6K1 activity, demonstrating that Arg-II also stimulates S6K1 in aging |
| 22928666 | Our study reveals a novel mechanism of mutual positive regulation between S6K1 and Arg-II in endothelial inflammation and aging |
| 22928666 | Targeting S6K1 and/or Arg-II may decelerate vascular aging and age-associated cardiovascular disease development |
| 19545540 | In old cells, the mRNA expression of human amino acid transporter (hCAT)2B, the activity and protein expression of arginase II were upregulated indicated by enhanced urea, L-ornithine, and L-arginine consumption |
| 19545540 | Inhibition of arginase activity, or transfection with arginase II siRNA prevented L-arginine-accelerated senescence |
| 19545540 | The most possible explanation for the paradoxical acceleration of senescence by L-arginine so far may be the translational and posttranslational activation of arginase II |
| 19442115 | The trimethylated Lys4 occupies an elongated groove, formed by the highly conserved aromatic and hydrophobic residues of the PHD finger, whereas the adjacent groove accommodates Arg2 |
