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Mohan S, Patel H, Bolinaga J, et al. AMP-activated protein kinase regulates L-arginine mediated cellular responses. Nutr Metab (Lond). 2013;10(1):40doi: 10.1186/1743-7075-10-40.
Mohan, S., Patel, H., Bolinaga, J., & Soekamto, N. (2013). AMP-activated protein kinase regulates L-arginine mediated cellular responses. Nutrition & metabolism, 10(1), 40. https://doi.org/10.1186/1743-7075-10-40
Mohan, Srinidi, et al. "AMP-activated protein kinase regulates L-arginine mediated cellular responses." Nutrition & metabolism vol. 10,1 (2013): 40. doi: https://doi.org/10.1186/1743-7075-10-40
Mohan S, Patel H, Bolinaga J, Soekamto N. AMP-activated protein kinase regulates L-arginine mediated cellular responses. Nutr Metab (Lond). 2013 May 29;10(1):40. doi: 10.1186/1743-7075-10-40. PMID: 23718875; PMCID: PMC3680329.
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Nutr Metab (Lond). 2013 May 29;10(1):40. doi: 10.1186/1743-7075-10-40.

AMP-activated protein kinase regulates L-arginine mediated cellular responses.

Nutrition & metabolism

Srinidi Mohan, Harsh Patel, Jorge Bolinaga, Nathania Soekamto

Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of New England, 716 Stevens Avenue, Portland, ME 04103, USA.

PMID: 23718875 PMCID: PMC3680329 DOI: 10.1186/1743-7075-10-40

Abstract

BACKGROUND: Our prior study revealed the loss in short-term L-Arginine (ARG) therapeutic efficacy after continuous exposure; resulting in tolerance development, mediated by endothelial nitric oxide synthase (eNOS) down-regulation, secondary to oxidative stress and induced glucose accumulation. However, the potential factor regulating ARG cellular response is presently unknown.

METHOD: Human umbilical vein endothelial cells were incubated with 100 μM ARG for 2 h in buffer (short-term or acute), or for 7 days in culture medium and challenged for 2 h in buffer (continuous or chronic), in the presence or absence of other agents. eNOS activity was determined by analyzing cellular nitrite/nitrate (NO2-/NO3-), and AMP-activated protein kinase (AMPK) activity was assayed using SAMS peptide. 13C6 glucose was added to medium to measure glucose uptake during cellular treatments, which were determined by LC-MS/MS. Cellular glucose was identified by o-toluidine method. Superoxide (O2•-) was identified by EPR-spin-trap, and peroxynitrite (ONOO-) was measured by flow-cytometer using aminophenyl fluorescein dye.

RESULTS: Short-term incubation of cells with 100 μM ARG in the presence or absence of 30 μM L-NG-Nitroarginine methyl ester (L-NAME) or 30 μM AMPK inhibitor (compound C, CMP-C) increased cellular oxidative stress and overall glucose accumulation with no variation in glucose transporter-1 (GLUT-1), or AMPK activity from control. The increase in total NO2-/NO3- after 2 h 100 μM ARG exposure, was suppressed in cells co-incubated with 30 μM CMP-C or L-NAME. Long-term exposure of ARG with or without CMP-C or L-NAME suppressed NO2-/NO3-, glucose uptake, GLUT-1, AMPK expression and activity below control, and increased overall cellular glucose, O2•- and ONOO-. Gluconeogenesis inhibition with 30 μM 5-Chloro-2-N-2,5-dichlorobenzenesulfonamido-benzoxazole (CDB) during ARG exposure for 2 h maintained overall cellular glucose to control, but increased cellular glucose uptake. Continuous co-incubation with CDB and ARG increased NO2-/NO3-, glucose uptake, GLUT-1, AMPK expression and activity, and maintained overall cellular glucose, O2•- and ONOO- to control conditions.

CONCLUSION: The present study provides the fundamental evidence for AMPK as the primary modulator of ARG cellular responses and for regulating the mode of glucose accumulation during short-term and continuous ARG treatments.

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