The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction

Research output: Contribution to journalShort survey

19 Citations (Scopus)

Abstract

The endothelial production of nitric oxide (NO) mediates endothelium-dependent vasorelaxation and restrains vascular inflammation, smooth muscle cell proliferation, and platelet aggregation. Impaired production of NO is a hallmark of endothelial dysfunction and promotes the development of cardiovascular disease. In endothelial cells, NO is generated by endothelial nitric oxide synthase (eNOS) through the conversion of its substrate, L-arginine to L-citrulline. Reduced access to L-arginine has been proposed as a major mechanism underlying reduced eNOS activity and NO production in cardiovascular disease. The arginases (Arg1 and Arg2) metabolize L-arginine to generate L-ornithine and urea and increased expression of arginase has been proposed as a mechanism of reduced eNOS activity secondary to the depletion of L-arginine. Indeed, supplemental L-arginine and suppression of arginase activity has been shown to improve endothelium-dependent relaxation and ameliorate cardiovascular disease. However, this simple relationship is complicated by observations that L-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. Accordingly, the subcellular compartmentalization of intracellular L-arginine into poorly interchangeable pools has been proposed to allow for the local depletion of pools or pockets of L-arginine. In agreement with this, there is considerable evidence supporting the importance of the subcellular localization of L-arginine metabolizing enzymes. In endothelial cells in vitro and in vivo, eNOS is found in discrete intracellular locations and the capacity to generate NO is heavily influenced by its localization inside the cell. Arg1 and Arg2 also reside in different subcellular environments and are thought to differentially influence endothelial function. The plasma membrane solute transporter, CAT-1 and the arginine recycling enzyme, arginosuccinate lyase, co-localize with eNOS and facilitate NO release. Herein, we highlight the importance of the subcellular location of eNOS and arginine transporting and metabolizing enzymes to NO release and cardiovascular disease.

Original languageEnglish (US)
Article numberArticle 184
JournalFrontiers in immunology
Volume4
Issue numberJUL
DOIs
StatePublished - Sep 16 2013

Fingerprint

Arginine
Nitric Oxide Synthase Type III
Nitric Oxide
Enzymes
Arginase
Cardiovascular Diseases
Endothelial Cells
Endothelium
Citrulline
Cell Aggregation
Lyases
Ornithine
Membrane Transport Proteins
Platelet Aggregation
Vascular Smooth Muscle
Vasodilation
Smooth Muscle Myocytes
Urea
Cell Proliferation
Cell Membrane

Keywords

  • ASL
  • ASS
  • Arginase
  • CAT-1
  • L-arginine
  • L-citrulline
  • Nitric
  • eNOS

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The subcellular compartmentalization of arginine metabolizing enzymes and their role in endothelial dysfunction. / Chen, Feng; Lucas, Rudolf; Fulton, David.

In: Frontiers in immunology, Vol. 4, No. JUL, Article 184, 16.09.2013.

Research output: Contribution to journalShort survey

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abstract = "The endothelial production of nitric oxide (NO) mediates endothelium-dependent vasorelaxation and restrains vascular inflammation, smooth muscle cell proliferation, and platelet aggregation. Impaired production of NO is a hallmark of endothelial dysfunction and promotes the development of cardiovascular disease. In endothelial cells, NO is generated by endothelial nitric oxide synthase (eNOS) through the conversion of its substrate, L-arginine to L-citrulline. Reduced access to L-arginine has been proposed as a major mechanism underlying reduced eNOS activity and NO production in cardiovascular disease. The arginases (Arg1 and Arg2) metabolize L-arginine to generate L-ornithine and urea and increased expression of arginase has been proposed as a mechanism of reduced eNOS activity secondary to the depletion of L-arginine. Indeed, supplemental L-arginine and suppression of arginase activity has been shown to improve endothelium-dependent relaxation and ameliorate cardiovascular disease. However, this simple relationship is complicated by observations that L-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. Accordingly, the subcellular compartmentalization of intracellular L-arginine into poorly interchangeable pools has been proposed to allow for the local depletion of pools or pockets of L-arginine. In agreement with this, there is considerable evidence supporting the importance of the subcellular localization of L-arginine metabolizing enzymes. In endothelial cells in vitro and in vivo, eNOS is found in discrete intracellular locations and the capacity to generate NO is heavily influenced by its localization inside the cell. Arg1 and Arg2 also reside in different subcellular environments and are thought to differentially influence endothelial function. The plasma membrane solute transporter, CAT-1 and the arginine recycling enzyme, arginosuccinate lyase, co-localize with eNOS and facilitate NO release. Herein, we highlight the importance of the subcellular location of eNOS and arginine transporting and metabolizing enzymes to NO release and cardiovascular disease.",
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