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ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis.

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  • 2014-12-09
Published in:
  • Autophagy. - 2014
AKT/PKB, v-akt murine thymoma viral oncogene homolog 1
ANOVA, analysis of variance
AR, aortic roots
ARG1, arginase 1
ARG2, arginase 2
ARGINASE
Atg, autophagy-related
BEC, S-12 bromoethyl-L-cystine-HCl
BECN1, Beclin 1, autophagy-related
Baf A1, bafilomycin A1
CMV, cytomegalovirus
EC, endothelial cell
H160F, inactive mutant of mouse ARG2
HAEC, human aortic endothelial cells
HUVEC, human umbilical vein endothelial cells
LC3, microtubule-associated protein 1 light chain 3
LDL, low-density lipoprotein
MTOR
MTOR, mechanistic target of rapamycin
NOS3/eNOS, nitric oxide synthase 3 (endothelial cell)
PE, phosphatidylethanolamine
PRKAA
PRKAA/AMPK, protein kinase, AMP-activated, α catalytic subunit
PtdIns3K, phosphatidylinositol 3-kinase
RPS6, ribosomal protein S6
RPS6KB1/S6K1, ribosomal protein S6 kinase, 70kDa, polypeptide 1
SA-ß-gal, senescence-associated-β-gal
SMC, smooth muscle cells
SQSTM1/p62, sequestosome 1
TP53/p53, tumor protein 53
Three-MA, 3-methyladenine
ULK1, unc-51 like autophagy activating kinase 1
VWF, von Willebrand factor
WT, wild type
apoe−/−, Apolipoprotein E-deficient
arg2−/−, arginase type II deficient
atherosclerosis
autophagy
endothelial cells
nor-NOHA, Nω-hydroxy-nor-Arginine
senescence
shRNA, short hairpin RNA
AMP-Activated Protein Kinases
Animals
Arginase
Atherosclerosis
Autophagy
Cellular Senescence
Diet, High-Fat
Humans
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice, Transgenic
Multiprotein Complexes
Signal Transduction
TOR Serine-Threonine Kinases
English Impaired autophagy function and enhanced ARG2 (arginase 2)-MTOR (mechanistic target of rapamycin) crosstalk are implicated in vascular aging and atherosclerosis. We are interested in the role of ARG2 and the potential underlying mechanism(s) in modulation of endothelial autophagy. 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, α catalytic subunit). Expression of an inactive ARG2 mutant (H160F) had the same effect. Moreover, silencing RPS6KB1 or expression of a constitutively active PRKAA prevented autophagy suppression by ARG2 or H160F. 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. 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. 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/123842
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