The red blood cell: a new key player in cardiovascular homoeostasis? Focus on the nitric oxide pathway

2014 ◽  
Vol 42 (4) ◽  
pp. 996-1000 ◽  
Author(s):  
Benedetta Porro ◽  
Sonia Eligini ◽  
Isabella Squellerio ◽  
Elena Tremoli ◽  
Viviana Cavalca
Keyword(s):  
Nitric Oxide ◽  
Blood Cells ◽  
Tissue Oxygenation ◽  
Blood Rheology ◽  
Amino Acid Transporters ◽  
Arginine Metabolism ◽  
Cationic Amino Acid ◽  
Physiological Processes ◽  
Oxide Synthase

RBCs (red blood cells) have a fundamental role in the regulation of vascular homoeostasis thanks to the ability of these cells to carry O2 (oxygen) between respiratory surfaces and metabolizing tissues and to release vasodilator compounds, such as ATP and NO (nitric oxide), in response to tissue oxygenation. More recently it has been shown that RBCs are also able to produce NO endogenously as they express a functional NOS (nitric oxide synthase), similar to the endothelial isoform. In addition, RBCs carry important enzymes and molecules involved in L-arginine metabolism, such as arginase, NO synthesis inhibitors and the cationic amino acid transporters. Altogether these findings strongly support the role of these cells as producers, vehicles and scavengers of NO, therefore affecting several physiological processes such as blood rheology and cell adhesion. Consequently, the importance of alterations in the L-arginine/NO metabolic pathway induced by specific conditions, e.g. oxidative stress, in different pathological settings have been investigated. In the present review we discuss the role of RBCs in vascular homoeostasis, focusing our attention on the importance of the NO pathway alterations in cardiovascular diseases and their relationship to major risk factors.

Role of dietary fish oil on nitric oxide synthase activity and oxidative status in mice red blood cells

2014 ◽  
Vol 5 (12) ◽  
pp. 3208-3215 ◽  
Author(s):  
Marcela A. Martins ◽  
Monique B. Moss ◽  
Iara K. S. Mendes ◽  
Márcia B. Águila ◽  
Carlos Alberto Mandarim-de-Lacerda ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fatty Acids ◽  
Nitric Oxide Synthase ◽  
Fish Oil ◽  
Blood Cells ◽  
Oxidative Status ◽  
Dietary Fish ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity

The consumption of n-3 polyunsaturated fatty acids derived from fish oil is associated with cardiovascular benefits, which may result from the participation of nitric oxide.

scholarly journals Threshold levels of extracellularl-arginine that trigger NOS-mediated ROS/RNS production in cardiac ventricular myocytes

2017 ◽  
Vol 312 (2) ◽  
pp. C144-C154 ◽  
Author(s):  
Jayalakshmi Ramachandran ◽  
R. Daniel Peluffo
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Ventricular Myocytes ◽  
Threshold Value ◽  
Amino Acid Transporters ◽  
Terminal Electron Acceptor ◽  
Cationic Amino Acid ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Harmful Effects

l-Arginine (L-Arg) is the substrate for nitric oxide synthase (NOS) to produce nitric oxide (NO), a signaling molecule that is key in cardiovascular physiology and pathology. In cardiac myocytes, L-Arg is incorporated from the circulation through the functioning of system-y+cationic amino acid transporters. Depletion of L-Arg leads to NOS uncoupling, with O2rather than L-Arg as the terminal electron acceptor, resulting in superoxide formation. The reactive oxygen species (ROS) superoxide (O2˙−), combined with NO, may lead to the production of the reactive nitrogen species (RNS) peroxynitrite (ONOO–), which is recognized as a major contributor to myocardial depression. In this study we aimed to determine the levels of external L-Arg that trigger ROS/RNS production in cardiac myocytes. To this goal, we used a two-step experimental design in which acutely isolated cardiomyocytes were loaded with the dye coelenterazine that greatly increases its fluorescence quantum yield in the presence of ONOO–and O2˙−. Cells were then exposed to different concentrations of extracellular L-Arg and changes in fluorescence were followed spectrofluorometrically. It was found that below a threshold value of ~100 µM, decreasing concentrations of L-Arg progressively increased ONOO–/ O2˙−-induced fluorescence, an effect that was not mimicked by d-arginine or l-lysine and was fully blocked by the NOS inhibitor l-NAME. These results can be explained by NOS aberrant enzymatic activity and provide an estimate for the levels of circulating L-Arg below which ROS/RNS-mediated harmful effects arise in cardiac muscle.

scholarly journals Transmembrane signalling mechanisms regulating expression of cationic amino acid transporters and inducible nitric oxide synthase in rat vascular smooth muscle cells

1999 ◽  
Vol 344 (1) ◽  
pp. 265-272 ◽  
Author(s):  
Anwar R. BAYDOUN ◽  
Samantha M. WILEMAN ◽  
Caroline P. D. WHEELER-JONES ◽  
Michael S. MARBER ◽  
Giovanni E. MANN ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Amino Acid ◽  
Nitric Oxide Synthase ◽  
P38 Mapk ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Arginine Transport ◽  
Ifn Γ ◽  
Oxide Synthase

The signalling mechanisms involved in the induction of nitric oxide synthase and L-arginine transport were investigated in bacterial lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-stimulated rat cultured aortic smooth muscle cells (RASMCs). The expression profile of transcripts for cationic amino acid transporters (CATs) and their regulation by LPS and IFN-γ were also examined. Control RASMCs expressed mRNA for CAT-1, CAT-2A and CAT-2B. Levels of all three transcripts were significantly elevated in activated cells. Stimulated CAT mRNA expression and L-arginine transport occurred independently of protein kinase C (PKC), protein tyrosine kinase (PTK) and p44/42 mitogen-activated kinases (MAPKs), but were inhibited by the p38 MAPK inhibitor SB203580, which at 3 μM caused maximum inhibition of both responses. Induction of NO synthesis was independent of p44/42 MAPK activation and only marginally dependent on PKC, but was attenuated markedly by the PTK inhibitors genistein and herbimycin A. SB203580 differentially regulated inducible NO synthase expression and NO production, potentiating both processes at low micromolar concentrations and inhibiting at concentrations of ⩾ 1 μM. In conclusion, our results suggest that RASMCs constitutively express transcripts for CAT-1, CAT-2A and CAT-2B, and that expression of these transcripts is significantly enhanced by LPS and IFN-γ. Moreover, stimulation of L-arginine transport and induction of NO synthesis by LPS and IFN-γ appear to be under critical regulation by the p38 MAPK, since both processes were significantly modified by SB203580 at concentrations so far shown to have no effect on other signalling pathways. Thus, in RASMCs, the p38 MAPK cascade represents an important signalling mechanism, regulating both enhanced L-arginine transport and induced NO synthesis.

Hypothermia attenuates iNOS, CAT-1, CAT-2, and nitric oxide expression in lungs of endotoxemic rats

2002 ◽  
Vol 283 (6) ◽  
pp. L1231-L1238 ◽  
Author(s):  
Philip O. Scumpia ◽  
Paul J. Sarcia ◽  
Vincent G. DeMarco ◽  
Bruce R. Stevens ◽  
Jeffrey W. Skimming
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Lung Injury ◽  
Lung Tissue ◽  
Inos Mrna ◽  
Amino Acid Transporters ◽  
Oxide Formation ◽  
Cationic Amino Acid ◽  
Nitric Oxide Formation ◽  
Oxide Synthase

Endotoxemia stimulates endogenous nitric oxide formation, induces transcription of arginine transporters, and causes lung injury. Hypothermia inhibits nitric oxide formation and is used as a means of organ preservation. We hypothesized that hypothermia inhibits endotoxin-induced intrapulmonary nitric oxide formation and that this inhibition is associated with attenuated transcription of enzymes that regulate nitric oxide formation, such as inducible nitric oxide synthase (iNOS) and the cationic amino acid transporters 1 (CAT-1) and 2 (CAT-2). Rats were anesthetized and randomized to treatment with hypothermia (18–24°C) or normothermia (36–38°C). Endotoxin was administered intravascularly. Concentrations of iNOS, CAT-1, CAT-2 mRNA, iNOS protein, and nitrosylated proteins were measured in lung tissue homogenates. We found that hypothermia abrogated the endotoxin-induced increase in exhaled nitric oxide and lung tissue nitrotyrosine concentrations. Western blot analyses revealed that hypothermia inhibited iNOS, but not endothelial nitric oxide synthase, protein expression in lung tissues. CAT-1, CAT-2, and iNOS mRNA concentrations were lower in the lungs of hypothermic animals. These findings suggest that hypothermia protects against intrapulmonary nitric oxide overproduction and nitric oxide-mediated lung injury by inhibiting transcription of iNOS, CAT-1, and CAT-2.

scholarly journals Arginine metabolism: nitric oxide and beyond

1998 ◽  
Vol 336 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Guoyao WU ◽  
Sidney M. MORRIS
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Amino Acid Transporters ◽  
Cdna Clones ◽  
Arginine Metabolism ◽  
Animal Cells ◽  
Argininosuccinate Synthase ◽  
Oxide Synthase ◽  
E Mail

Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified complex patterns of interaction among these enzymes. There is growing interest in the potential roles of the arginase isoenzymes as regulators of the synthesis of nitric oxide, polyamines, proline and glutamate. Physiological roles and relationships between the pathways of arginine synthesis and catabolism in vivo are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ (e.g. liver, small intestine and kidney) and subcellular (cytosol and mitochondria) levels, as well as to changes in expression during development and in response to diet, hormones and cytokines. The ongoing development of new cell lines and animal models using cDNA clones and genes for key arginine metabolic enzymes will provide new approaches more clearly elucidating the physiological roles of these enzymes. Correspondence may be addressed to either Dr. G. Wu (e-mail [email protected]) or Dr. S. M. Morris, Jr. (e-mail [email protected]) at the addresses given.

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