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Cell-specific pleiotropic effects of arginase-II on obesity-associated metabolic and vascular disorders

English title Cell-specific pleiotropic effects of arginase-II on obesity-associated metabolic and vascular disorders
Applicant Yang Zhihong
Number 159582
Funding scheme Project funding
Research institution Division de Physiologie Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Cardiovascular Research
Start/End 01.07.2015 - 28.02.2019
Approved amount 474'000.00
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Keywords (6)

mTOR; Inflammation ; Macrophage ; Arginase-II ; Obesity; Vascular Dysfunction

Lay Summary (German)

Lead
Arginase ist ein Protein-Enzym, welches die Aminosäure L-Arginin abbaut. Zwei Typen von Arginase existieren. d.h. Arginase-I (Arg-I) und Arginase-II (Arg-II). Arg-I ist exprimiert in der Leber und ist essential für die Ammoniak-Entgiftung für unseren Körper. Arg-II ist exprimiert und induzierbar in anderen Organen oder Zellen, einschließlich Gefässzellen und entzündlichen Makrophagen und fördert chronische Entzündungskrankheiten wie z.B. Zuckerkrankheit bei Fettleibigkeit und die assoziierte vaskuläre Komplikationen. Unsere neuen Arbeiten zeigten, dass Arg-II die Wirkungen in Makrophagen und Gefässzellen hat, die nicht mit L-Arginin-Stoffwechsel zusammenhängen müssen. Die Mechanismen sind noch nicht bekannt.
Lay summary

Dieses Projekt hat vor, die molekularen Mechanismen zu untersuchen, wie Arg-II in Entzündungszellen nämlich Makrophagen funktioniert und wie es die Funktion der Zelle und die Entzündung des Körpers reguliert. Das heisst, wir werden abklären, welche Wirkungen von Arg-II in den Makrophagen von der Enzym-Aktivität abhängig sind und welche davon unabhängig sind; Ob die Wirkungen vor allem die von der Enzym-Aktivität unabhängigen Wirkungen von Arg-II zu Krankheiten wie Zuckerkrankheit und Gefässkomplikationen bei Fettleibigkeit beitragen. Die endgültigen Ergebnisse des Projekts werden die neuen Funktionen von Arg-II bei der Entstehung des Adipositas-assoziierten Diabetes und bei den Gefässkomplikationen aufdecken. Die erwarteten Ergebnisse würden darauf hinweisen, dass Runterregulierung der Arg-II-Expression wirksamer sei als die Hemmung der enzymatischen Aktivität von Arg-II, um die Adipositas-assoziierten Erkrankungen und die Gefässkomplikationen zu behandeln.

 

Direct link to Lay Summary Last update: 16.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Role of tubular epithelial arginase-II in renal inflammaging
Huang Ji, Liang Xiujie, Ladeiras Diogo, Fellay Benoit, Ming Xiu-Fen, Yang Zhihong (2021), Role of tubular epithelial arginase-II in renal inflammaging, in npj Aging and Mechanisms of Disease, 7(1), 5-5.
Detrimental Effects of Chronic L-Arginine Rich Food on Aging Kidney
Huang Ji, Ladeiras Diogo, Yu Yi, Ming Xiu-Fen, Yang Zhihong (2021), Detrimental Effects of Chronic L-Arginine Rich Food on Aging Kidney, in Frontiers in Pharmacology, 11, 1-13.
Arginase‐II promotes melanoma migration and adhesion through enhancing hydrogen peroxide production and STAT3 signaling
Yu Yi, Ladeiras Diogo, Xiong Yuyan, Boligan Kayluz Frias, Liang Xiujie, Gunten Stephan, Hunger Robert E., Ming Xiu‐Fen, Yang Zhihong (2020), Arginase‐II promotes melanoma migration and adhesion through enhancing hydrogen peroxide production and STAT3 signaling, in Journal of Cellular Physiology, 235(12), 9997-10011.
Inhibition of p38mapk Reduces Adipose Tissue Inflammation in Aging Mediated by Arginase-II
Huang Ji, Liu Chang, Ming Xiu-Fen, Yang Zhihong (2020), Inhibition of p38mapk Reduces Adipose Tissue Inflammation in Aging Mediated by Arginase-II, in Pharmacology, 105(9-10), 491-504.
Myosin 1b Regulates Nuclear AKT Activation by Preventing Localization of PTEN in the Nucleus
Yu Yi, Xiong Yuyan, Ladeiras Diogo, Yang Zhihong, Ming Xiu-Fen (2019), Myosin 1b Regulates Nuclear AKT Activation by Preventing Localization of PTEN in the Nucleus, in iScience, 19, 39-53.
Hypoxia Enhances Endothelial Intercellular Adhesion Molecule 1 Protein Level Through Upregulation of Arginase Type II and Mitochondrial Oxidative Stress
Liang Xiujie, Arullampalam Prakash, Yang Zhihong, Ming Xiu-Fen (2019), Hypoxia Enhances Endothelial Intercellular Adhesion Molecule 1 Protein Level Through Upregulation of Arginase Type II and Mitochondrial Oxidative Stress, in Frontiers in Physiology, 10(105), 491.
Arginase-II negatively regulates renal aquaporin-2 and water reabsorption
Huang Ji, Montani Jean-Pierre, Verrey François, Feraille Eric, Ming Xiu-Fen, Yang Zhihong (2018), Arginase-II negatively regulates renal aquaporin-2 and water reabsorption, in The FASEB Journal, 32(10), 5520-5531.
Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis
Yu Yi, Xiong Yuyan, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2018), Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis, in Cell Death & Disease, 9(3), 313-313.
Kidney Mass Reduction Leads to l ‐Arginine Metabolism‐Dependent Blood Pressure Increase in Mice
Pillai Samyuktha Muralidharan, Seebeck Petra, Fingerhut Ralph, Huang Ji, Ming Xiu‐Fen, Yang Zhihong, Verrey François (2018), Kidney Mass Reduction Leads to l ‐Arginine Metabolism‐Dependent Blood Pressure Increase in Mice, in Journal of the American Heart Association, 7(5), e008025.
Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling
Zhu Cuicui, Yu Yi, Montani Jean-Pierre, Ming Xiu-Fen, Yang Zhihong (2017), Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling, in BMC Research Notes, 10(1), 82-82.
Arginase-II Deficiency Extends Lifespan in Mice
Xiong Yuyan, Yepuri Gautham, Montani Jean-Pierre, Ming Xiu-Fen, Yang Zhihong (2017), Arginase-II Deficiency Extends Lifespan in Mice, in Frontiers in Physiology, 8, 682.
Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging
Xiong Yuyan, Yepuri Gautham, Necetin Sevil, Montani Jean-Pierre, Ming Xiu-Fen, Yang Zhihong (2017), Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging, in Diabetes, 66(6), 1636-1649.
Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression
Reiner Martin F., Akhmedov Alexander, Stivala Simona, Keller Stephan, Gaul Daniel S., Bonetti Nicole R., Savarese Gianluigi, Glanzmann Martina, Zhu Cuicui, Ruf Wolfram, Yang Zhihong, Matter Christian M., Lüscher Thomas F., Camici Giovanni G., Beer Juerg H. (2017), Ticagrelor, but not clopidogrel, reduces arterial thrombosis via endothelial tissue factor suppression, in Cardiovascular Research, 113(1), 61-69.
Adventitia and perivascular adipose tissue – the integral unit in vascular disease
Yang Zhihong, Ming Xiu-Fen (2017), Adventitia and perivascular adipose tissue – the integral unit in vascular disease, in Magnus Bäck, Krams Robert (ed.), OXFORD University Press, OXFORD, 309.
Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity
Huang Ji, Rajapakse Angana, Xiong Yuyan, Montani Jean-Pierre, Verrey François, Ming Xiu-Fen, Yang Zhihong (2016), Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity, in Frontiers in Physiology, 7, 560.
Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation
Liu Chang, Rajapakse Angana G., Riedo Erwin, Fellay Benoit, Bernhard Marie-Claire, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2016), Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation, in Scientific Reports, 6(1), 20405-20405.
En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries
Yu Yi, Xiong Yuyan, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2016), En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries, in Journal of Visualized Experiments, (108), 53718.
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Klionsky Daniel J, Abdelmohsen Kotb, Abe Akihisa, Abedin Md Joynal, Abeliovich Hagai, Acevedo Arozena Abraham, Adachi Hiroaki, Adams Christopher M, Adams Peter D, Adeli Khosrow, Adhihetty Peter J, Adler Sharon G, Agam Galila, Agarwal Rajesh, Aghi Manish K, Agnello Maria, Agostinis Patrizia, Aguilar Patricia V, Aguirre-Ghiso Julio, Airoldi Edoardo M, Ait-Si-Ali Slimane, Akematsu Takahiko, Akporiaye Emmanuel T, Al-Rubeai Mohamed, et al. (2016), Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), in Autophagy, 12(1), 1-222.

Collaboration

Group / person Country
Types of collaboration
Prof. Stephan von Gunten/University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Thomas F. Lüscher/University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Francois Verrey Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Urs Albrecht/University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Cardiovascular Biology Meeting Poster Hypoxia enhances endothelial ICAM-1 expression through upregulation of arginase-II and mitochondrial oxidative stress 14.03.2019 Fribourg, Switzerland Yang Zhihong; Liang Xiujie;
LS2 Annual Meeting Talk given at a conference Roles of Arginase-II in vascular endothelial inflammation under hypoxic condition 14.02.2019 Zürich, Switzerland Liang Xiujie; Yang Zhihong;
LS2 Annual Meeting Poster Myosin 1b regulates nuclear Akt activation through preventing localization of PTEN in the nucleus 14.02.2019 Zurich, Switzerland Yang Zhihong;
LS2 Annual Meeting Poster Arginase-II promotes pre-adipocyte to release IL-6 through p38mapk leading to vascular endothelial inflammation in aging 14.02.2019 Zürich, Switzerland Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis 05.09.2018 Bern, Switzerland Yu Yi; Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Roles of Arginase-II in vascular endothelial inflammation under hypoxic condition 04.09.2018 Fribourg , Switzerland Liang Xiujie; Yang Zhihong;
Swiss Physiological Society Annual Meeting Talk given at a conference Myosin 1b regulates nuclear Akt activation through preventing localization of PTEN in the nucleus 04.09.2018 Fribourg , Switzerland Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Role of arginase-II in melanoma growth and metastasis 04.09.2018 Fribourg, Switzerland Ladeiras Diogo; Yang Zhihong; Yu Yi;
Swiss Physiological Society Annual Meeting Poster Arginase-II deficiency prevents age-related renal inflammation and fibrosis 04.09.2018 Fribourg, Switzerland Ladeiras Diogo; Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Arginase-II negatively regulates renal aquaporin-2 and water reabsorption 04.09.2018 Fribourg , Switzerland Yang Zhihong;
Cardiovascular Biology Meeting Talk given at a conference Arginase-II activates mTORC1 through myosin-1b in vascular cell senescence and apoptosis 15.03.2018 Fribourg, Switzerland Yu Yi; Yang Zhihong;
8th NCCR kidney.ch Retreat Poster Arginase-II negatively regulates renal aquaporin-2 and water reabsorption 09.02.2018 Murten, Switzerland Yang Zhihong;
FEPS Poster Role of arginase-II in regulation of water balance 13.09.2017 Vienna, Austria Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Role of arginase-II in regulation of renal aquaporin-2 and water reabsorption 05.09.2017 Bern, Switzerland Yang Zhihong;
7th NCCR kidney.ch Retreat Poster Role of arginase-II in regulation of water balance 09.02.2017 Murten, Switzerland Yang Zhihong;
LS2 Annual Meeting Poster Role of arginase-II in regulation of aging 02.02.2017 Zurich, Switzerland Yang Zhihong;
LS2 Annual Meeting Talk given at a conference Role of arginase-II in regulation of water balance 02.02.2017 Zürich, Switzerland Yang Zhihong;
6th the Joint Cardiovascular and Metabolic Research Meeting Poster Role of arginase-II in regulation of water balance 19.01.2017 Fribourg , Switzerland Yang Zhihong;
Cardiovascular and Metabolic Research Meeting Talk given at a conference Role of arginase-II in regulation of aging. 19.01.2017 Fribourg, Switzerland Yang Zhihong;
Swiss Physiological Society Annual Meeting Poster Arginase-II in preadipocytes promotes IL-6 production through p38mapk leading to vascular endothelial inflammatory activation in aging 06.09.2016 Fribourg, Switzerland Yu Yi; Yang Zhihong;
Swiss Physiological Society Annual Meeting Talk given at a conference Genetic Targeting of Arginase-II Gene Prevents Renal Injury in Diet-Induced Obesity 06.09.2016 Fribourg, Switzerland Yang Zhihong;
6th International Kidney.CH Symposium Poster Genetic Targeting of Arginase-II Gene Prevents Renal Injury in Diet-Induced Obesity 01.06.2016 Zürich, Switzerland Yang Zhihong;
6th International Kidney.CH Symposium Poster Role of arginase-II in regulation of water balance 01.06.2016 Zürich, Switzerland Yang Zhihong;
84th EAS congress Poster P38 Mitogen-Activated Protein Kinase is Involved in Arginase-II-mediated eNOS-uncoupling in Aging and Obesity 29.05.2016 Innsbruck, Austria Yang Zhihong; Yu Yi;
6th NCCR kidney.ch Retreat Poster Role of arginase-II in regulation of aquaporin 2 (AQP2) in the aging kidney 25.02.2016 Murten, Switzerland Yang Zhihong;
Cardiovascular and Metabolic Research Meeting Talk given at a conference Arginase-II promotes tumor necrosis factor-alpha release from pancreatic acinar cells causing β-cell apoptosis in aging. 14.01.2016 Fribourg , Switzerland Yang Zhihong;
Swiss Physiological Society Annual Meeting Talk given at a conference Arginase-II impairs endothelial autophagy through mTOR signaling in advanced atherosclerosis 08.09.2015 Fribourg, Switzerland Yang Zhihong; Yu Yi;
Swiss Physiological Society Annual Meeting Talk given at a conference Role of p38 Mitogen-Activated Protein Kinase in Vascular Endothelial Aging: Interaction with Arginase-II and S6K1 Signaling Pathway 08.09.2015 Fribourg , Switzerland Yang Zhihong; Yu Yi;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Bahnbrechende Erkenntnisse zur Altersdiabetes Freiburger Nachrichten Western Switzerland 2017
Media relations: print media, online media New discovery of an age-related diabetes mechanism Uni-Press International Western Switzerland 2017
Media relations: print media, online media Autophagie: Saubermachen in der Zelle. Uni-Presse International Western Switzerland 2015
Print (books, brochures, leaflets) Der Geist sitzt im Herzen. Interview by Zürich Heart House German-speaking Switzerland 2015
Print (books, brochures, leaflets) Vascular investigations – Age and Arginase. International 2015

Awards

Title Year
Vigener Prize in Life Science 2018
Poster Prize at FEPS meeting 2017
EAS Fellowship 2016

Associated projects

Number Title Start Funding scheme
141070 S6K1, arginase-II, and vascular endothelial aging 01.04.2012 Project funding
141070 S6K1, arginase-II, and vascular endothelial aging 01.04.2012 Project funding

Abstract

Background: Arginase, the L-arginine-ureahydrolase, metabolizes L-arginine to urea and L-ornithine. Two isoenzymes i.e., arginase-I (Arg-I) and arginase-II (Arg-II) exist. While Arg-I is mainly expressed in the liver for ammonia detoxification, Arg-II is expressed in extrahepatic cells including vascular cells and macrophages, participating in chronic inflammatory diseases, e.g., insulin resistance and atherosclerosis, which is believed to be due to L-arginine depletion for nitric oxide (NO) production. However, our recent research suggests that Arg-II promotes macrophage pro-inflammatory responses under the disease conditions independently of inducible NO-synthase in macrophages, impairs endothelial autophagy (a self-repairing mechanism), causes smooth muscle cell apoptosis/senescence through mTORC2-Akt-mTORC1-S6K1 signalling independently of its L-arginine metabolizing activity (pleiotropic function). Research aims: Given the importance of mTORC1-S6K1 in insulin resistance and the pro-inflammatory role of Arg-II in macrophage, we wish to elucidate the molecular mechanisms of the pleiotropic function of Arg-II in mTOR signaling and dissect the macrophage-specific role of Arg-II’s enzymatic activity-dependent and -independent effects in obesity-associated insulin resistance and vascular dysfunction. Scientific relevance: The final results of this project will not only elucidate molecular mechanisms of the discovered novel pleiotropic Arg-II function in activation of mTORC2-Akt-mTORC1-S6K1 signalling pathway, which is independent of its L-arginine metabolizing activity, but will also for the first time provide new insights into the specific contribution of WT and/or inactive Arg-II in macrophages to obesity-associated inflammation, insulin resistance, and vascular dysfunction. The expected results, if proved, would suggest that targeting Arg-II expression rather than enzymatic activity would be more effective to treat obesity-associated insulin resistance and vascular complications.
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