Knockdown of Arginase I Restores NO Signaling in the Vasculature of Old Rats

White, Anthony R.; Ryoo, Sungwoo; Li, Dechun; Champion, Hunter C.; Steppan, Jochen; Wang, Danming; Nyhan, Daniel; Shoukas, Artin A.; Hare, Joshua M.; Berkowitz, Dan E.

doi:10.1161/01.hyp.0000198543.34502.d7

Cited by 161 publications

(152 citation statements)

References 48 publications

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“…Two additional NO synthase isoforms exist in mammals, neuronal NO synthase (nNOS; encoded by Nos1) and endothelial NO synthase (encoded by Nos3), which may benefit from L-citrulline metabolism. Arginase activity regulates NO output in endothelial cells during hypertension and in aged rodents (31)(32)(33). Furthermore, it was suggested that endothelial NO synthase relies on L-arginine synthesis from L-citrulline to mediate optimal NO production (34,35).…”

Section: Discussionmentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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Microbicidal NO production is reliant on inducible NO synthase–mediated l-arginine metabolism in macrophages (MΦs). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography–tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette–Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in l-arginine. Furthermore, we found that arginase-expressing MΦs preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

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Section: Discussionmentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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“…For RT-PCR, total RNA from rat heart and isolated myocytes was prepared by homogenization in the presence of Trizol reagent (GIBCO), and RT-PCR was performed with specific Arg I and II primers, as described (52).…”

Section: Methodsmentioning

confidence: 99%

“…NO production was evaluated by measuring nitrite levels (Calbiochem) after preincubation of heart and myocytes with BEC (10 mol͞liter) in PBS (pH 7.4), as described (52).…”

Section: Methodsmentioning

confidence: 99%

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Steppan

Ryoo

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoformspecific regulation. One regulatory mechanism for NOS is substrate (L-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes L-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-L-cysteine (BEC) augmented Ca 2؉ -dependent NOS activity and NO production in myocytes, which did not depend on extracellular L-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxynor-L-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N G -nitro-L-arginine methyl ester and S-methyl-L-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted. mitochondria ͉ L-arginine pools ͉ spatial confinement

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“…The main functions of endothelial cells include the inhibition of blood coagulation, control of vascular wall tension, control of angiogenesis and inflammatory and immune processes. In light of the role of the epithelium in both the synthesis and release of several hormonal compounds, it may be considered to be the largest endocrine organ in the human body [54]. The principal substances released by endothelial cells include [51,54]:  endothelin 1 -responsible, e.g., for vasoconstriction,  prostacyclin -responsible primarily for vasodilatation and inhibition of platelet aggregation,  nitrogen oxide (NO) -responsible for vasodilation, inhibition of platelet aggregation and inhibition of platelet adhesion,  von Willebrand factor (vWF) -stimulating blood coagulation and platelet adhesion,  tissue thromboplastin and thrombomodulin -activating blood coagulation,  interleukins (IL-2, IL-3, IL-6) -responsible for proliferation and differentiation of immune system cells,  tissue plasminogen activator (TPA) -responsible for the control of fibrinolysis.…”

Section: Endothelium -Histological Structure and Significancementioning

confidence: 99%

“…They activate antithrombin, heparin co-factor, the lipoprotein lipase, inhibitors of the exogenous clotting system and platelet factor 4. Upon analysis of the ultrastructure, endothelial cells were seen to form junctions with the assistance of cadherin 5 (CD144) and MACAM-1 (CD146) [54]. Integrin receptors are manifested in their basolateral parts, which bind the endothelium to components of the basement membrane and extracellular matrix, with collagen, glycosaminoglycans, fibronectin, elastin, vitronectin, laminin or thrombospondin.…”

Section: Endothelium -Histological Structure and Significancementioning

confidence: 99%

The Contribution of Endothelial Marker Proteins in the Determination of Vascular Angiogenic Potential, in Normal Physiological Conditions and in Neoplasia

Konwerska

Janik

Malińska

et al. 2011

Advances in Cell Biology

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Summary: Recently, the most significant studies in the field of angiogenesis are related to trials concerning the evaluation of the prognostic significance of endothelial markers. By using an estimation of the expression of endothelial cell markers, immunohistochemical studies can assess for the continuity of the vascular intima, as well as allow for the distinction of early, late and mature forms of endothelial cells. The determination of the endothelial cell phenotype using markers such as CD34, CD31, CD133, e-NOS and von Willebrand factor may provide a valuable tool for the monitoring of both normal physiology as well as neoplastic diseases.

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Knockdown of Arginase I Restores NO Signaling in the Vasculature of Old Rats

Cited by 161 publications

References 48 publications

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

The Contribution of Endothelial Marker Proteins in the Determination of Vascular Angiogenic Potential, in Normal Physiological Conditions and in Neoplasia

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