Journal
AUTOPHAGY
Volume 10, Issue 12, Pages 2223-2238Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/15548627.2014.981789
Keywords
ARGINASE; atherosclerosis; autophagy; endothelial cells; MTOR; PRKAA; senescence
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Funding
- Swiss National Science Foundation [310030_141070/1]
- Swiss Heart Foundation
- National Center of Competence in Research Program (NCCR-Kidney.CH)
- Chinese Scholarship Council
- Swiss National Science Foundation (SNF) [310030_141070] Funding Source: Swiss National Science Foundation (SNF)
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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, a 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.
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