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Lilian Hortale De Oliveira Moreira - One of the best experts on this subject based on the ideXlab platform.
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Arginase 1 expression in granulomas of tuberculosis patients
Fems Immunology and Medical Microbiology, 2012Co-Authors: Ana P. Pessanha, Rodrigo A. P. Martins, Albanita Vianna, Ana Luiza Mattosguaraldi, Lilian Hortale De Oliveira MoreiraAbstract:Mycobacterium tuberculosis (Mtb) is an intracellular pathogen able to survive and multiply within macrophages. Several mechanisms allow this bacterium to escape macrophage microbicidal activity. Mtb may interfere with the ability of mouse macrophages to produce antibactericidal nitric oxide, by inducing the expression of Arginase 1 (Arg1). It remains unclear whether this pathway has a role in humans infected with Mtb. In this study, we investigated the expression of Arg1 in granulomas of human lung tissues from patients with tuberculosis. We show that Arg1 is expressed not only in granuloma-associated macrophages, but also in type II pneumocytes.
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Arginase‐1 expression in granulomas of tuberculosis patients
FEMS immunology and medical microbiology, 2012Co-Authors: Ana P. Pessanha, Rodrigo A. P. Martins, Ana Luíza Mattos-guaraldi, Albanita Vianna, Lilian Hortale De Oliveira MoreiraAbstract:Mycobacterium tuberculosis (Mtb) is an intracellular pathogen able to survive and multiply within macrophages. Several mechanisms allow this bacterium to escape macrophage microbicidal activity. Mtb may interfere with the ability of mouse macrophages to produce antibactericidal nitric oxide, by inducing the expression of Arginase 1 (Arg1). It remains unclear whether this pathway has a role in humans infected with Mtb. In this study, we investigated the expression of Arg1 in granulomas of human lung tissues from patients with tuberculosis. We show that Arg1 is expressed not only in granuloma-associated macrophages, but also in type II pneumocytes.
Ruth B. Caldwell - One of the best experts on this subject based on the ideXlab platform.
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Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell Arginase 1.
Cardiovascular research, 2017Co-Authors: Anil Bhatta, Zsolt Bagi, Lin Yao, Haroldo A. Toque, Jijun Chen, Reem T. Atawia, Abdelrahman Y. Fouda, Rudolf Lucas, Ruth B. CaldwellAbstract:Aims Elevation of Arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive Arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of Arginase 1 expression within the vascular endothelial cells in this pathology. Methods and results To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific Arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an Arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular Arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of Arginase 1 or ABH treatment. Conclusion Vascular dysfunctions in diet-induced obesity are prevented by deletion of Arginase 1 in vascular endothelial cells or Arginase inhibition. These findings indicate that upregulation of Arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.
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Abstract 14793: Obesity-induced Inflammation of the Visceral Adipose Tissue is Mediated by Upregulation of Arginase 1 in Vascular Endothelial Cells
Circulation, 2016Co-Authors: Lin Yao, Zsolt Bagi, Anil Bhatta, Rudolf Lucas, Ruth B. Caldwell, Yuqing Huo, Robert W. CaldwellAbstract:Obesity-induced cardiovascular dysfunction involves pathological expansion of visceral adipose tissue (VAT). Our previous studies have shown that Arginase 1 (A1) expression in vascular endothelial ...
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Role of Arginase 1 in Diabetes-Induced Senescence of Endothelial Cells and Macrophages
The FASEB Journal, 2015Co-Authors: Esraa Shosha, S. Priya Narayanan, Tahira Lemtalsi, Ji Xing, Robert W. Caldwell, Ruth B. CaldwellAbstract:Cellular senescence has been considered as a contributing factor to diabetes related complications. The present study was undertaken to evaluate involvement of the ureahydrolase enzyme Arginase 1 (...
Zsolt Bagi - One of the best experts on this subject based on the ideXlab platform.
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Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell Arginase 1.
Cardiovascular research, 2017Co-Authors: Anil Bhatta, Zsolt Bagi, Lin Yao, Haroldo A. Toque, Jijun Chen, Reem T. Atawia, Abdelrahman Y. Fouda, Rudolf Lucas, Ruth B. CaldwellAbstract:Aims Elevation of Arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive Arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of Arginase 1 expression within the vascular endothelial cells in this pathology. Methods and results To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific Arginase 1 knockout (EC-A1-/-) and littermate controls(A1con) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an Arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular Arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of Arginase 1 or ABH treatment. Conclusion Vascular dysfunctions in diet-induced obesity are prevented by deletion of Arginase 1 in vascular endothelial cells or Arginase inhibition. These findings indicate that upregulation of Arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.
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Abstract 14793: Obesity-induced Inflammation of the Visceral Adipose Tissue is Mediated by Upregulation of Arginase 1 in Vascular Endothelial Cells
Circulation, 2016Co-Authors: Lin Yao, Zsolt Bagi, Anil Bhatta, Rudolf Lucas, Ruth B. Caldwell, Yuqing Huo, Robert W. CaldwellAbstract:Obesity-induced cardiovascular dysfunction involves pathological expansion of visceral adipose tissue (VAT). Our previous studies have shown that Arginase 1 (A1) expression in vascular endothelial ...
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Selective up-regulation of Arginase-1 in coronary arteries of diabetic patients.
Frontiers in immunology, 2013Co-Authors: Zsolt Bagi, Attila Feher, Huijuan Dou, Zuzana BroskovaAbstract:Coronary artery disease (CAD) remains the leading cause of death in the Western societies. Diabetes mellitus (DM) is one of the highly prevalent diseases, which remarkably accelerates the development of CAD. Experimental evidence indicates that decreased bioavailability of coronary endothelial nitric oxide (NO) contributes to the development of CAD in DM. There are recent studies showing that a selective impairment of NO synthesis occurs in coronary arteries of DM patients, which is mainly due to the limited availability of endothelial NO synthase (eNOS) precursor, L-arginine. Importantly, these studies demonstrated that DM, independent of the presence of CAD, leads to selective up-regulation of Arginase 1. Arginase 1 seems to play an important role in limiting L-arginine availability in the close proximity of eNOS in vessels of DM patients. This brief review examines recent clinical studies demonstrating the pathological role of vascular Arginase 1 in human diabetes. Whether Arginase 1, which is crucial in the synthesis of various fundamental polyamines in the body, will represent a potent therapeutic target for prevention of DM-associated CAD is still debated.
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Arginase 1 Contributes to Diminished Coronary Arteriolar Dilation in Patients with Diabetes
American journal of physiology. Heart and circulatory physiology, 2011Co-Authors: Timea Beleznai, Attila Feher, David Spielvogel, Steven L. Lansman, Zsolt BagiAbstract:Arginase 1, via competing with nitric oxide (NO) synthase for the substrate l-arginine, may interfere with NO-mediated vascular responses. We tested the hypothesis that Arginase 1 contributes to co...
Colin D Funk - One of the best experts on this subject based on the ideXlab platform.
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Transplantation of Gene-Edited Hepatocyte-like Cells Modestly Improves Survival of Arginase-1-Deficient Mice.
Molecular therapy. Nucleic acids, 2017Co-Authors: Yuan Yan Sin, Laurel L Ballantyne, Christopher R. Richmond, Colin D FunkAbstract:Progress in gene editing research has been accelerated by utilizing engineered nucleases in combination with induced pluripotent stem cell (iPSC) technology. Here, we report transcription activator-like effector nuclease (TALEN)-mediated reincorporation of Arg1 exons 7 and 8 in iPSCs derived from Arginase-1-deficient mice possessing Arg1Δ alleles lacking these terminal exons. The edited cells could be induced to differentiate into hepatocyte-like cells (iHLCs) in vitro and were subsequently used for transplantation into our previously described (Sin et al., PLoS ONE 2013) tamoxifen-inducible Arg1-Cre Arginase-1-deficient mouse model. While successful gene-targeted repair was achieved in iPSCs containing Arg1Δ alleles, only minimal restoration of urea cycle function could be observed in the iHLC-transplanted mice compared to control mice, and survival in this lethal model was extended by up to a week in some mice. The partially rescued phenotype may be due to inadequate regenerative capacity of Arginase-1-expressing cells in the correct metabolic zones. Technical hurdles exist and will need to be overcome for gene-edited iPSC to iHLC rescue of Arginase-1 deficiency, a rare urea cycle disorder.
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Proof-of-Concept Gene Editing for the Murine Model of Inducible Arginase-1 Deficiency.
Scientific reports, 2017Co-Authors: Yuan Yan Sin, Laurel L Ballantyne, Phillipe R. Price, Colin D FunkAbstract:Arginase-1 deficiency in humans is a rare genetic disorder of metabolism resulting from a loss of Arginase-1, leading to impaired ureagenesis, hyperargininemia and neurological deficits. Previously, we generated a tamoxifen-inducible Arginase-1 deficient mouse model harboring a deletion of Arg1 exons 7 and 8 that leads to similar biochemical defects, along with a wasting phenotype and death within two weeks. Here, we report a strategy utilizing the Clustered, Regularly Interspaced, Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system in conjunction with piggyBac technology to target and reincorporate exons 7 and 8 at the specific Arg1 locus in attempts to restore the function of Arginase-1 in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) and macrophages in vitro. While successful gene targeted repair was achieved, minimal urea cycle function was observed in the targeted iHLCs compared to adult hepatocytes likely due to inadequate maturation of the cells. On the other hand, iPSC-derived macrophages expressed substantial amounts of "repaired" Arginase. Our studies provide proof-of-concept for gene-editing at the Arg1 locus and highlight the challenges that lie ahead to restore sufficient liver-based urea cycle function in patients with urea cycle disorders.
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Liver-specific knockout of Arginase-1 leads to a profound phenotype similar to inducible whole body Arginase-1 deficiency.
Molecular genetics and metabolism reports, 2016Co-Authors: Laurel L Ballantyne, Yuan Yan Sin, Osama Y. Al-dirbashi, David J. Hurlbut, Colin D FunkAbstract:Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype. Liver-selective Arg1 deletion was induced by using an adeno-associated viral (AAV)-thyroxine binding globulin (TBG) promoter-Cre recombinase vector administered to Arg1 “floxed” mice; Arg1fl/fl). An AAV vector expressing an Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes after partial hepatectomy was used for cell delivery to “rescue” tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout of Arg1 with lethality ≈ 3 weeks after Cre-induced gene disruption. Delivery of Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival > 4 months) but a significant proportion still succumb to the enzyme deficiency even though liver expression and enzyme activity of the fusion protein reach levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT hepatocytes into knockout livers can be achieved but not sufficient for rescuing the lethal phenotype. This raises a conundrum relating to liver-specific expression of Arg1. On the one hand, loss of expression in this organ appears to be both necessary and sufficient to explain the lethal phenotype of the genetic disorder in mice. On the other hand, gene and cell-directed therapies suggest that rescue of extra-hepatic Arg1 expression may also be necessary for disease correction. Further studies are needed in order to illuminate the detailed mechanisms for pathogenesis of Arg1-deficiency.
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Arginase-1 deficiency
Journal of Molecular Medicine, 2015Co-Authors: Garrett Baron, Andreas Schulze, Colin D FunkAbstract:Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. Gene transfer studies in these mice are revealing potential therapeutic options that can be exploited in the future. However, caution is advised in extrapolating results since the lethal disease phenotype in mice is much more severe than in humans indicating that the mouse models may not precisely recapitulate human disease etiology. Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. Lingering questions and future areas to be addressed relating to the clinical manifestations of ARG1 deficiency in liver and brain are also presented. Hopefully, this review will spark invigorated research efforts that lead to treatments with better clinical outcomes.
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strategies to rescue the consequences of inducible Arginase 1 deficiency in mice
PLOS ONE, 2015Co-Authors: Laurel L Ballantyne, Yuan Yan Sin, Tim St Amand, Steven Goossens, Lieven Haenebalcke, Jody J Haigh, Lianna Kyriakopoulou, Andreas Schulze, Colin D FunkAbstract:Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced Arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for Arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible Arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible Arginase-1 knockout mouse strain. Delivery of an Arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue Arginase-1 deficient mice to any great extent. Since the induced Arginase-1 deficient mouse model displays a much more severe phenotype when compared to human Arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.
John M. Routes - One of the best experts on this subject based on the ideXlab platform.
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Correction: Possible Role of Arginase-1 in Concomitant Tumor Immunity
PloS one, 2016Co-Authors: Michael J. Korrer, Yuwen Zhang, John M. RoutesAbstract:Dr. Yuwen Zhang should be included in the author byline. Dr. Zhang should be listed as the second author and is affiliated with #1–5: 1 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 2 Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 3 Children's Research Institute, Milwaukee, Wisconsin, United States of America; 4 Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America; 5 Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202. The contributions of this author are as follow: Performed the experiments and analyzed the data. The correct citation is: Korrer MJ, Zhang Y, Routes JM (2014) Possible Role of Arginase-1 in Concomitant Tumor Immunity. PLoS ONE 9(3): e91370. doi:10.1371/journal.pone.0091370
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Possible Role of Arginase-1 in Concomitant Tumor Immunity
PloS one, 2014Co-Authors: Michael J. Korrer, John M. RoutesAbstract:The expression of Adenovirus serotype 2 or serotype 5 (Ad2/5) E1A in tumor cells reduces their tumorigenicity in vivo by enhancing the NK cell mediated and T cell mediated anti-tumor immune response, an activity that correlates with the ability of E1A to bind p300. We determined if E1A could be used as a molecular adjuvant to enhance antigen-specific T cell responses to a model tumor antigen, ovalbumin (OVA). To achieve this goal, we stably expressed a fusion protein of E1A and OVA (MCA-205-E1A-OVA), OVA (MCA-205-OVA) or a mutant version of E1A unable to bind p300 and OVA (E1A-Δp300-OVA) in the B6-derived, highly tumorigenic MCA-205 tumor cell line. MCA-205-E1A-OVA tumor cells were over 10,000 fold less tumorigenic than MCA-205-OVA, MCA-205-E1A-Δp300-OVA, or MCA-205 in B6 mice. However, immunization of B6 mice with live MCA-205-OVA, MCA-205-E1A-Δp300-OVA and MCA-E1A-OVA tumor cells induced nearly equivalent OVA-specific CD4 T cells and CD8 CTL responses. Further studies revealed that mice with primary, enlarging MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumors on one flank exhibited OVA-specific anti-tumor T cell responses that rejected a tumorigenic dose of MCA-205-OVA cells on the contralateral flank (concomitant tumor immunity). Next we found that tumor associated macrophages (TAMs) in progressive MCA-205-OVA tumors, but not MCA-205-E1A-OVA tumors that expressed high levels of Arginase-1, which is known to have local immunosuppressive activities. In summary, immunization of mice with MCA-205 cells expressing OVA, E1A-Δp300-OVA or E1A-OVA induced equivalent OVA-specific CD4 and CD8 anti-tumor responses. TAMs found in MCA-205-OVA, but not MCA-205-E1A-OVA, tumors expressed high levels of Arginase-1. We hypothesize that the production of Arginase-1 by TAMs in MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumor cells leads to an ineffective anti-tumor immune response in the tumor microenvironment, but does not result in inhibition of a systemic anti-tumor immunity.