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Sidney M. Morris - One of the best experts on this subject based on the ideXlab platform.
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Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3 dependent mechanism
Kidney International, 2013Co-Authors: Hanning You, Sidney M. Morris, Ting Gao, Timothy K Cooper, Alaa S AwadAbstract:Recently, we showed that pharmacological blockade or genetic deficiency of Arginase-2 confers kidney protection in diabetic mouse models. Here, we tested whether the protective effect of Arginase inhibition is nitric oxide synthase 3 (eNOS) dependent in diabetic nephropathy. Experiments were conducted in eNOS-knockout and their wild-type littermate mice using multiple low doses of vehicle or streptozotocin, and treated with continuous subcutaneous infusion of vehicle or the Arginase inhibitor S-(2-boronoethyl)-L-cysteine by an osmotic pump. Inhibition of Arginases for 6 weeks in diabetic wild-type mice significantly attenuated albuminuria, the increase in plasma creatinine and blood urea nitrogen, histopathological changes, kidney fibronectin and TNF-α expression, kidney macrophage recruitment, and oxidative stress compared with vehicle-treated diabetic wild-type mice. Arginase inhibition in diabetic eNOS-knockout mice failed to affect any of these parameters, but reduced kidney macrophage recruitment and kidney TNF-α expression compared with vehicle-treated diabetic eNOS-knockout mice. Furthermore, diabetic wild-type and eNOS-knockout mice exhibited increased kidney Arginase-2 protein, Arginase activity, and ornithine levels. Thus, Arginase inhibition mediates renal tissue protection in diabetic nephropathy by an eNOS-dependent mechanism and has an eNOS-independent effect on kidney macrophage recruitment.
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Arginase 2 mediates diabetic renal injury
Diabetes, 2011Co-Authors: Sidney M. Morris, Diane Kepkalenhart, Ting Gao, Timothy K Cooper, Alaa S AwadAbstract:OBJECTIVE To determine 1 ) whether renal Arginase activity or expression is increased in diabetes and 2 ) whether Arginase plays a role in development of diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS The impact of Arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2 Akita mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and Arginase-2–deficient mice ( Arg2 −/− ). RESULTS Pharmacological blockade or genetic deficiency of Arginase-2 conferred kidney protection in Ins2 Akita mice or STZ-induced diabetic renal injury. Blocking Arginases using S -(2-boronoethyl)-l-cysteine for 9 weeks in Ins2 Akita mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2 Akita mice. Furthermore, kidney Arginase-2 expression increased in Ins2 Akita mice compared with control. In contrast, Arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2 −/− mice mimicked Arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney Arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2 −/− mice. The increase in kidney Arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2 −/− mice. CONCLUSIONS These findings indicate that Arginase-2 plays a major role in induction of diabetic renal injury and that blocking Arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN.
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Determination of mammalian Arginase activity.
Methods in enzymology, 2008Co-Authors: Diane Kepka-lenhart, David E. Ash, Sidney M. MorrisAbstract:Of all arginine catabolic enzymes, the Arginases and nitric oxide (NO) synthases are the ones that are of greatest interest to many investigators. Mammalian Arginases catalyze the hydrolysis of arginine to ornithine and urea and are composed of two distinct isozymes: Arginase I, located within the cytosol, and Arginase II, located within mitochondria. The Arginases not only can inhibit NO synthesis by reducing arginine availability, but also can promote the synthesis of polyamines or proline via production of the common precursor ornithine. Because of their inducibility in many cell types and to their potential impact on multiple biochemical pathways in health and disease, there is growing interest in assays of Arginase activity. Although Arginase activity may be determined by either spectrophotometric or radiochemical assays, radiochemical assays afford greater sensitivity and do not require correction for any ornithine or urea that may be present in the samples. Part of the Arginase assay protocol described in this chapter also can be used for radiochemical assays of enzymes that catalyze decarboxylation reactions. No activity assay currently available is capable of distinguishing the Arginase isozymes.
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induction of Arginase i transcription by il 4 requires a composite dna response element for stat6 and c ebpβ
Gene, 2005Co-Authors: Michael J Gray, Mirjana Poljakovic, Diane Kepkalenhart, Sidney M. MorrisAbstract:Arginine metabolism in macrophages during infection and inflammation is complex, owing to differential regulation of inducible nitric oxide synthase (iNOS) and Arginases by cytokines and other agents. Changes in levels of Th2 cytokines such as interleukin-4 (IL-4) can play important roles in these conditions via effects on arginine metabolism. IL-4 alters macrophage arginine metabolism by inducing Arginase I expression and inhibiting nitric oxide production. To determine the molecular basis for induction of Arginase I, the promoter of the murine Arginase I gene was cloned and analyzed by transfection in RAW 264.7 macrophage cells. IL-4 induction required a composite response element containing STAT6 and C/EBP sites located 2.86 kb upstream of the transcription start site. Competition experiments showed that STAT6 and C/EBPbeta bind to the STAT6 and C/EBP sites non-cooperatively. Elucidation of the mechanisms involved in regulation of Arginase I transcription may provide a basis for developing strategies to modulate Arginase expression in Th2 cytokine-predominant diseases.
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elevated Arginase i expression in rat aortic smooth muscle cells increases cell proliferation
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Liu Hua Wei, Sidney M. Morris, Louis J IgnarroAbstract:Abstract Arginase, which exists as the isoforms Arginase I and II, catalyzes the hydrolysis of arginine to ornithine and urea. Ornithine is the principal precursor for production of polyamines, which are required for cell proliferation. Rat aortic smooth muscle cells (RASMC) contain constitutive Arginase I, and Arginase inhibitors cause inhibition of cell proliferation. The objective of this study was to determine whether the elevated expression of Arginase I in RASMC causes increased cell proliferation. RASMC were stably transfected with either rat Arginase I cDNA or a β-galactosidase control expression plasmid. Western blots and Arginase enzymatic assays revealed high-level expression of cytosolic Arginase I in Arginase I-transfected RASMC. Moreover, this observation was associated with the increased production of urea and polyamines and higher rates of RASMC proliferation. The two selective inhibitors of Arginase, NG-hydroxy-l-arginine and S-(2-boronoethyl)-l-cysteine, inhibited Arginase and decreased the production of urea and polyamines in Arginase I-transfected RASMC, all of which were associated with the inhibition of cell proliferation. This study demonstrates that elevated Arginase I expression increases RASMC proliferation by mechanisms involving increased production of polyamines. These observations suggest that Arginase I plays a potentially important role in controlling RASMC proliferation.
Jl Boucher - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Arginase II modulates nitric-oxide synthesis through nonfreely exchangeable L-arginine pools in human endothelial cells.
J Pharmacol Exp Ther, 2006Co-Authors: Gökce Topal, Jl Boucher, Annie Brunet, Laurence Walch, Monique David-dufilhoAbstract:Reduced synthesis of nitric oxide (NO) contributes to the endothelial dysfunction and may be related to limited availability of L-arginine, the common substrate of constitutive nitric-oxide synthase (NOS) and cytosolic Arginase I and mitochondrial Arginase II. To determine whether Arginases modulate the endothelial NO synthesis, we investigated the effects of the competitive Arginase inhibitor N(omega)-hydroxy-nor-L-arginine (Nor-NOHA) on the activity of NOS, Arginases, and L-arginine transporter and on NO release at surface of human umbilical vein endothelial cells (HUVECs). In unstimulated cells, Nor-NOHA dose-dependently reduced the Arginase activity with maximal inhibition at 20 microM. When HUVECs were stimulated by thrombin without extracellular L-arginine, Nor-NOHA dose-dependently increased the NOS activity and the NO release with maximal effects at 20 microM. Extracellular L-arginine also dose-dependently increased NO release and Arginase activity. When HUVECs were stimulated by thrombin in the presence of 100 microM L-arginine, NOS activity and NO release were similar in untreated and Nor-NOHA-treated cells. However, despite activation of L-arginine uptake, the inhibition of Arginase activity by Nor-NOHA was still significant. The depletion of freely exchangeable L-arginine pools with extracellular L-lysine did not prevent Nor-NOHA from increasing the NO release. This indicates the presence of pools, which are accessible to NOS and Arginase, but not exchangeable. Interestingly, the mitochondrial Arginase II was constitutively expressed, whereas the cytosolic Arginase I was barely detectable in HUVECs. These data suggest that endothelial NO synthesis depends on the activity of Arginase II in mitochondria and l-arginine carriers in cell membrane.
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nitric oxide biosynthesis nitric oxide synthase inhibitors and Arginase competition for l arginine utilization
Cellular and Molecular Life Sciences, 1999Co-Authors: Jl Boucher, C. Moali, Jp TenuAbstract:Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by Nω-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.
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Nitric oxide biosynthesis, nitric oxide synthase inhibitors and Arginase competition for L-arginine utilization.
Cellular and Molecular Life Sciences, 1999Co-Authors: Jl Boucher, C. Moali, Jp TenuAbstract:Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by N(omega)-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by N(omega)-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.
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N omega-hydroxyamino-alpha-amino acids as a new class of very strong inhibitors of Arginases
Springer Verlag, 1996Co-Authors: Custot J., Jl Boucher, Vadon S., Guedes C., Dijols S., Delaforge M., Mansuyd XxxxAbstract:International audienceThe effects of various compounds bearing an N-OH group such as N-hydroxy-guanidines, amidoximes, and hydroxylamines, on bovine and rat liver Arginases was studied. Some of these compounds with an L-a-amino acid function at an appropriate distance from the N-OH group acted as strong competitive liver Arginase inhibitors, displaying Ki values between 4 and 150 mu M. Two compounds, N-epsilon-hydroxy-L-lysine and N(omega)hydroxy-D,L-indospicine, which exhibited Ki values of 4 and 20 mu M (at pH 7.4), were the most potent inhibitors of Arginase described to date. The distance between the alpha-amino acid and N-OH functions appeared to be crucial for potent inhibition of Arginase, as N-delta-hydroxy-L-ornithine, which has one -CH2 group less than N-epsilon-hydroxy-L-lysine, exhibited a 37-fold higher Ki value than N-epsilon-hydroxy-L-lysine. Based on these results, a model for the interaction of N-omega-hydroxyamino-L-cramino acids with the Arginase active site is proposed. This model involves the binding of the N-OH group of the inhibitors to the Arginase Mn(II) center and suggests that N-epsilon-hydroxy-L-lysine is a good transition state analog of Arginase.The effects of various compounds bearing an N-OH group such as N-hydroxy-guanidines, amidoximes, and hydroxylamines, on bovine and rat liver Arginases was studied. Some of these compounds with an L-a-amino acid function at an appropriate distance from the N-OH group acted as strong competitive liver Arginase inhibitors, displaying Ki values between 4 and 150 mu M. Two compounds, N-epsilon-hydroxy-L-lysine and N(omega)hydroxy-D,L-indospicine, which exhibited Ki values of 4 and 20 mu M (at pH 7.4), were the most potent inhibitors of Arginase described to date. The distance between the alpha-amino acid and N-OH functions appeared to be crucial for potent inhibition of Arginase, as N-delta-hydroxy-L-ornithine, which has one -CH2 group less than N-epsilon-hydroxy-L-lysine, exhibited a 37-fold higher Ki value than N-epsilon-hydroxy-L-lysine. Based on these results, a model for the interaction of N-omega-hydroxyamino-L-cramino acids with the Arginase active site is proposed. This model involves the binding of the N-OH group of the inhibitors to the Arginase Mn(II) center and suggests that N-epsilon-hydroxy-L-lysine is a good transition state analog of Arginase
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N omega-hydroxyamino-alpha-amino acids as a new class of very strong inhibitors of Arginases
Journal of Biological Inorganic Chemistry, 1996Co-Authors: J. Custot, Jl Boucher, S. Vadon, C. Guedes, S. Dijols, M. Delaforge, Xxxx MansuydAbstract:The effects of various compounds bearing an N-OH group such as N-hydroxy-guanidines, amidoximes, and hydroxylamines, on bovine and rat liver Arginases was studied. Some of these compounds with an L-a-amino acid function at an appropriate distance from the N-OH group acted as strong competitive liver Arginase inhibitors, displaying Ki values between 4 and 150 mu M. Two compounds, N-epsilon-hydroxy-L-lysine and N(omega)hydroxy-D,L-indospicine, which exhibited Ki values of 4 and 20 mu M (at pH 7.4), were the most potent inhibitors of Arginase described to date. The distance between the alpha-amino acid and N-OH functions appeared to be crucial for potent inhibition of Arginase, as N-delta-hydroxy-L-ornithine, which has one -CH2 group less than N-epsilon-hydroxy-L-lysine, exhibited a 37-fold higher Ki value than N-epsilon-hydroxy-L-lysine. Based on these results, a model for the interaction of N-omega-hydroxyamino-L-cramino acids with the Arginase active site is proposed. This model involves the binding of the N-OH group of the inhibitors to the Arginase Mn(II) center and suggests that N-epsilon-hydroxy-L-lysine is a good transition state analog of Arginase.The effects of various compounds bearing an N-OH group such as N-hydroxy-guanidines, amidoximes, and hydroxylamines, on bovine and rat liver Arginases was studied. Some of these compounds with an L-a-amino acid function at an appropriate distance from the N-OH group acted as strong competitive liver Arginase inhibitors, displaying Ki values between 4 and 150 mu M. Two compounds, N-epsilon-hydroxy-L-lysine and N(omega)hydroxy-D,L-indospicine, which exhibited Ki values of 4 and 20 mu M (at pH 7.4), were the most potent inhibitors of Arginase described to date. The distance between the alpha-amino acid and N-OH functions appeared to be crucial for potent inhibition of Arginase, as N-delta-hydroxy-L-ornithine, which has one -CH2 group less than N-epsilon-hydroxy-L-lysine, exhibited a 37-fold higher Ki value than N-epsilon-hydroxy-L-lysine. Based on these results, a model for the interaction of N-omega-hydroxyamino-L-cramino acids with the Arginase active site is proposed. This model involves the binding of the N-OH group of the inhibitors to the Arginase Mn(II) center and suggests that N-epsilon-hydroxy-L-lysine is a good transition state analog of Arginase.
Céline Demougeot - One of the best experts on this subject based on the ideXlab platform.
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Effect of stroke on Arginase expression and localization in the rat brain
European Journal of Neuroscience, 2013Co-Authors: Aurore Quirie, Céline Demougeot, Christine Marie, Nathalie Bertrand, Claude Mossiat, Philippe Garnier, Anne Prigent-tessierAbstract:Because Arginase and nitric oxide (NO) synthases (NOS) compete to degrade l-arginine, Arginase plays a crucial role in the modulation of NO production. Moreover, the Arginase 1 isoform is a marker of M2 phenotype macrophages that play a key role in tissue remodeling and resolution of inflammation. While NO has been extensively investigated in ischemic stroke, the effect of stroke on the Arginase pathway is unknown. The present study focuses on Arginase expression/activity and localization before and after (1, 8, 15 and 30days) the photothrombotic ischemic stroke model. This model results in a cortical lesion that reaches maximal volume at day 1 post-stroke and then decreases as a result of astrocytic scar formation. Before stroke, Arginase 1 and 2 expressions were restricted to neurons. Stroke resulted in up-regulation of Arginase 1 and increased Arginase activity in the region centered on the lesion where inflammatory cells are present. These changes were associated with an early and long-lasting Arginase 1 up-regulation in activated macrophages and astrocytes and a delayed Arginase 1 down-regulation in neurons at the vicinity of the lesion. A linear positive correlation was observed between expressions of Arginase 1 and glial fibrillary acidic protein as a marker of activated astrocytes. Moreover, the pattern of Arginase 1 and brain-derived neurotrophic factor (BDNF) expressions in activated astrocytes was similar. Unlike Arginase 1, Arginase 2 expression was not changed by stroke. In conclusion, increased Arginase 1 expression is not restricted to macrophages in inflammation elicited by stroke but also occurs in activated astrocytes where it may contribute to neuroplasticity through the control of BDNF production.
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Misregulation of the Arginase pathway in tissues of spontaneously hypertensive rats.
Hypertension Research, 2009Co-Authors: Teddy Bagnost, Claire André, Yves Guillaume, Alain Berthelot, Magalie Alvergnas, Carole Miguet-alfonsi, Céline DemougeotAbstract:There is a growing evidence that Arginase has a role in the pathophysiology of cardiovascular diseases including hypertension. We recently reported Arginase upregulation in aortas from hypertensive spontaneously hypertensive rats (SHRs). The aim of this study was to determine whether Arginase abnormalities occur in other tissues of SHR, including the target organs of hypertension. Experiments were conducted on 5-, 10-, 19- and 26-week-old SHRs and Wistar-Kyoto (WKY) rats. Arginase activity and expression were evaluated in heart, kidney, liver, lung and brain tissue extracts. To investigate the role of blood pressure by itself in Arginase abnormalities, Arginase activity was determined in 10-week-old SHRs previously treated with hydralazine (20 mg kg(-1) per day, for 5 weeks). Compared with WKY rats, cardiac Arginase activity was higher in hypertensive SHRs aged 10 weeks (+46%, P
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Time course of vascular Arginase expression and activity in spontaneously hypertensive rats.
Life Sciences, 2007Co-Authors: Céline Demougeot, Anne Prigent-tessier, Teddy Bagnost, Claire André, Yves Guillaume, Malika Bouhaddi, Christine Marie, Alain BerthelotAbstract:There is growing evidence that vascular Arginase plays a role in pathophysiology of vascular diseases. We recently reported high Arginase activity/expression in young adult hypertensive spontaneously hypertensive rats (SHR). The aim of the present study was to characterize the time course of Arginase pathway abnormalities in SHR and to explore the contributing role of hemodynamics and inflammation. Experiments were conducted on 5, 10, 19 and 26-week-old SHR and their age-matched control Wistar Kyoto (WKY) rats. Arginase activity as well as expression of Arginase I, Arginase II, endothelial and inducible NOS were determined in aortic tissue extracts. Levels of L-arginine, NO catabolites and IL-6 (a marker of inflammation) were measured in plasma. Arginase activity/expression was also measured in 10-week-old SHR previously treated with hydralazine (20 mg/kg/day, per os, for 5 weeks). As compared to WKY, SHR exhibited high vascular Arginase I and II expression from prehypertensive to established stages of hypertension. However, a mismatch between expression and activity was observed at the prehypertensive stage. Arginase expression was not related either to plasma IL-6 levels or to expression of NOS. Prevention of hypertension by hydralazine significantly blunted Arginase upregulation and restored Arginase activity. Importantly, Arginase activity and blood pressure (BP) correlated in SHR. In conclusion, our results demonstrate that Arginase upregulation precedes blood pressure rising and identify elevated blood pressure as a contributing factor of Arginase dysregulation in genetic hypertension. They also demonstrated a close relationship between Arginase activity and BP, thus making Arginase a promising target for antihypertensive therapy.
Alain Berthelot - One of the best experts on this subject based on the ideXlab platform.
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Misregulation of the Arginase pathway in tissues of spontaneously hypertensive rats.
Hypertension Research, 2009Co-Authors: Teddy Bagnost, Claire André, Yves Guillaume, Alain Berthelot, Magalie Alvergnas, Carole Miguet-alfonsi, Céline DemougeotAbstract:There is a growing evidence that Arginase has a role in the pathophysiology of cardiovascular diseases including hypertension. We recently reported Arginase upregulation in aortas from hypertensive spontaneously hypertensive rats (SHRs). The aim of this study was to determine whether Arginase abnormalities occur in other tissues of SHR, including the target organs of hypertension. Experiments were conducted on 5-, 10-, 19- and 26-week-old SHRs and Wistar-Kyoto (WKY) rats. Arginase activity and expression were evaluated in heart, kidney, liver, lung and brain tissue extracts. To investigate the role of blood pressure by itself in Arginase abnormalities, Arginase activity was determined in 10-week-old SHRs previously treated with hydralazine (20 mg kg(-1) per day, for 5 weeks). Compared with WKY rats, cardiac Arginase activity was higher in hypertensive SHRs aged 10 weeks (+46%, P
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Time course of vascular Arginase expression and activity in spontaneously hypertensive rats.
Life Sciences, 2007Co-Authors: Céline Demougeot, Anne Prigent-tessier, Teddy Bagnost, Claire André, Yves Guillaume, Malika Bouhaddi, Christine Marie, Alain BerthelotAbstract:There is growing evidence that vascular Arginase plays a role in pathophysiology of vascular diseases. We recently reported high Arginase activity/expression in young adult hypertensive spontaneously hypertensive rats (SHR). The aim of the present study was to characterize the time course of Arginase pathway abnormalities in SHR and to explore the contributing role of hemodynamics and inflammation. Experiments were conducted on 5, 10, 19 and 26-week-old SHR and their age-matched control Wistar Kyoto (WKY) rats. Arginase activity as well as expression of Arginase I, Arginase II, endothelial and inducible NOS were determined in aortic tissue extracts. Levels of L-arginine, NO catabolites and IL-6 (a marker of inflammation) were measured in plasma. Arginase activity/expression was also measured in 10-week-old SHR previously treated with hydralazine (20 mg/kg/day, per os, for 5 weeks). As compared to WKY, SHR exhibited high vascular Arginase I and II expression from prehypertensive to established stages of hypertension. However, a mismatch between expression and activity was observed at the prehypertensive stage. Arginase expression was not related either to plasma IL-6 levels or to expression of NOS. Prevention of hypertension by hydralazine significantly blunted Arginase upregulation and restored Arginase activity. Importantly, Arginase activity and blood pressure (BP) correlated in SHR. In conclusion, our results demonstrate that Arginase upregulation precedes blood pressure rising and identify elevated blood pressure as a contributing factor of Arginase dysregulation in genetic hypertension. They also demonstrated a close relationship between Arginase activity and BP, thus making Arginase a promising target for antihypertensive therapy.
Jp Tenu - One of the best experts on this subject based on the ideXlab platform.
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nitric oxide biosynthesis nitric oxide synthase inhibitors and Arginase competition for l arginine utilization
Cellular and Molecular Life Sciences, 1999Co-Authors: Jl Boucher, C. Moali, Jp TenuAbstract:Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by Nω-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.
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Nitric oxide biosynthesis, nitric oxide synthase inhibitors and Arginase competition for L-arginine utilization.
Cellular and Molecular Life Sciences, 1999Co-Authors: Jl Boucher, C. Moali, Jp TenuAbstract:Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by N(omega)-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and Arginases for L-arginine utilization, and by potent inhibition of Arginase activity by N(omega)-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.