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Title: The citrulline recycling pathway sustains cardiovascular function in arginine-depleted healthy mice, but cannot sustain nitric oxide production during endotoxin challenge

Author
item YUAN, YANG - Children'S Nutrition Research Center (CNRC)
item MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC)
item BETANCOURT, ANCIZAR - Baylor College Of Medicine
item DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC)
item YALLAMPALLI, CHANDRASEKHAR - Baylor College Of Medicine
item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/8/2018
Publication Date: 6/7/2018
Citation: Yuan, Y., Mohammad, M., Betancourt, A., Didelija, I.C., Yallampalli, C., Marini, J.C. 2018. The citrulline recycling pathway sustains cardiovascular function in arginine-depleted healthy mice, but cannot sustain nitric oxide production during endotoxin challenge. Journal of Nutrition. 148(6):844–850. https://dx.doi.org/10.1093/jn/nxy065.
DOI: https://doi.org/10.1093/jn/nxy065

Interpretive Summary: Arginine is an important amino acid involved in many physiological processes. Among these, arginine is the sole precursor for nitric oxide synthesis, a signal molecule implicated in the maintenance of blood pressure and immunity. Here we showed that a minor recycling intracellular pathway is able to maintain arginine availability for nitric oxide synthesis in the cardiovascular system and sustain blood pressure. However, when the demand for arginine is increased using a bacterial endotoxin this recycling pathway is unable to sustain nitric production synthesis by the immune system.

Technical Abstract: The recycling of citrulline by argininosuccinate synthase (ASS1) and lyase (ASL) is crucial to maintain arginine availability and nitric oxide (NO) production. Arginine deiminase (ADI-PEG20) is a bacterial enzyme used to deplete circulating arginine. The goal of this research was to test the hypothesis that citrulline is able to sustain intracellular arginine availability for NO production in ADI-PEG20 arginine-depleted mice. C57BL/6J 6-8 week old male mice injected with ADI-PEG20 (5 IU) or saline (control) were used in four different studies. Arginine, citrulline and NO kinetics were determined using stable isotopes in unchallenged (Study 1) and endotoxin-challenged mice (Study 2). Blood pressure was determined by telemetry for 6 days after ADI-PEG20 administration (Study 3); vasomotor activity, and ASS1 and ASL gene expression were determined in mesenteric arteries collected from additional animals (Study 4). ADI-PEG20 administration resulted in arginine depletion (<1 vs. 111+/-37 umol/L), but greater plasma citrulline concentrations (900+/-123 vs. 76+/-8 umol/L; P < 0.001) and fluxes (402+/-17 vs. 126+/-4 umol/kg-1/h-1; P < 0.001) than in controls. Endotoxin-challenged ADI-PEG20-treated mice produced less NO than controls (13+/-1 vs 27+/-2 umol/kg-1/h-1; P < 0.001). No differences (P > 0.50) were observed for cardiovascular parameters (heart rate, blood pressure) between ADI-PEG20-treated and control mice. Furthermore, no ex-vivo vasomotor differences were observed between the two treatments. ADI-PEG20 administration resulted in greater gene expression of ASS1 (~3 fold), but lower expression of ASL (30% reduction). ADI-PEG20 successfully depleted circulating arginine without any effect on cardio-vascular endpoints in healthy mice, but limited NO production after endotoxin challenge. Therefore, the citrulline recycling pathway can sustain local arginine availability independently from circulating arginine, satisfying the demand of arginine for endothelial NO production, but it is unable to do so when a high demand for arginine is elicited by endotoxin.