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S6K1, arginase-II, and vascular endothelial aging

English title S6K1, arginase-II, and vascular endothelial aging
Applicant Yang Zhihong
Number 141070
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 01.04.2012 - 30.06.2015
Approved amount 402'000.00
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Keywords (5)

Arginase-II ; Endothelial aging; eNOS ; S6K1; oxdative stress

Lay Summary (English)

Lead
Lay summary
Aging  instead the vasoprotective NO, a situation calledeNOS-uncoupling, is involved in vascular aging. Although studies suggest that enhancedarginase activity (arginase-II in humans and mice) causes eNOS-uncoupling, itis still debatable, whether this is due to depletion of L-arginine for eNOS. Importantly,chronic L-arginine supplementation paradoxically induces endothelial cell agingand increases mortality in patients with myocardial infarction or withperipheral artery disease. In addition, our study also shows that hyperactiveS6K1 emzymatic activity is present in aging endothelial cells and causes eNOS-uncoupling.It is, however, not known, how S6K1 causes eNOS-uncoupling and acceleratesendothelial aging. Based on these results, we would like to investigate theroles and molecular/biochemical mechanisms of S6K1 and Arg-II in promotion of eNOS-uncouplingand endothelial aging in cultured cells and animal models. .-2revious studies showed that the enzyme in vascularendothelial cells called endothelial nitric oxide synthase (eNOS) can produce toxicOis aprominent independent risk factor for cardiovascular disease, the underlyingmechanisms of aging-associated cardiovascular diseases are not fully understood, yet. PThis project will explore noval mechanisms ofage-associated cardiovascular diseases. Particularly, how L-arginine therapy isdetrimental for cardiovascular health will be answered. Expected results shall alsojustify therapeutic rationales of targeting S6K1 and Arg-II foraging-associated vascular disease and beyond, since eNOS-uncoupling, increasedS6K1 and enhanced Arg-II activity are also observed under various pathologicalconditions such as atherosclerosis and obesity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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 : JoVE, (108), 53718-53718.
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Klionsky Daniel J. (2016), Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), in Autophagy, 12(1 ), 1-222.
Role of p38 mitogen-activated protein kinase in vascular endothelial aging: interaction with Arginase-II and S6K1 signaling pathway.
Wu Zongsong, Yu Yi, Liu Chang, Xiong Yuyan, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2015), Role of p38 mitogen-activated protein kinase in vascular endothelial aging: interaction with Arginase-II and S6K1 signaling pathway., in Aging, 7(1), 70-81.
ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis.
Xiong Yuyan, Yepuri Gautham, Forbiteh Michael, Yu Yi, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2014), ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis., in Autophagy, 10(12), 2223-38.
Functions of arginase isoforms in macrophage inflammatory responses: impact on cardiovascular diseases and metabolic disorders.
Yang Zhihong, Ming Xiu-Fen (2014), Functions of arginase isoforms in macrophage inflammatory responses: impact on cardiovascular diseases and metabolic disorders., in Frontiers in immunology, 5, 533-533.
Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling.
Xiong Yuyan, Fru Michael Forbiteh, Yu Yi, Montani Jean-Pierre, Ming Xiu-Fen, Yang Zhihong (2014), Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling., in Aging, 6(5), 369-79.
p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-uncoupling in obesity.
Yu Yi, Rajapakse Angana G, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2014), p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-uncoupling in obesity., in Cardiovascular diabetology, 13, 113-113.
Arginase: The emerging therapeutic target for vascular oxidative stress and inflammation
Yang Zhihong, Ming Xiu Fen (2013), Arginase: The emerging therapeutic target for vascular oxidative stress and inflammation, in Frontiers in Immunology, 4(JUN), open-open.
Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability.
Xiong Yuyan, Yu Yi, Montani Jean-Pierre, Yang Zhihong, Ming Xiu-Fen (2013), Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability., in Journal of the American Heart Association, 2(4), 000096-000096.
Endothelial NF-κB: the remote controller of the backyard fire in the vascular wall?
Yang Zhihong (2013), Endothelial NF-κB: the remote controller of the backyard fire in the vascular wall?, in Cardiovascular research, 97(1), 8-9.
Functions and Mechanisms of arginase in age-associated cardiovascular diseases
Ming X-F, Yang Z (2013), Functions and Mechanisms of arginase in age-associated cardiovascular diseases, in Current Translational Geriatrics and Experimental Gerontology Reports , open(open), open-open.
Arginase II Promotes Macrophage Inflammatory Responses Through Mitochondrial Reactive Oxygen Species, Contributing to Insulin Resistance and Atherogenesis.
Ming Xiu-Fen, Rajapakse Angana G, Yepuri Gautham, Xiong Yuyan, Carvas João M, Ruffieux Jean, Scerri Isabelle, Wu Zongsong, Popp Katja, Li Jianhui, Sartori Claudio, Scherrer Urs, Kwak Brenda R, Montani Jean-Pierre, Yang Zhihong (2012), Arginase II Promotes Macrophage Inflammatory Responses Through Mitochondrial Reactive Oxygen Species, Contributing to Insulin Resistance and Atherogenesis., in Journal of the American Heart Association, 1(4), 000992-000992.
mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases.
Yang Z, Ming X-F (2012), mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases., in Obesity reviews : an official journal of the International Association for the Study of Obesity, 13 Suppl 2, 58-68.
p38 Mitogen-activated protein kinase is required for glucosamine-induced endothelial nitric oxide synthase uncoupling and plasminogen-activator inhibitor expression.
Wu Zongsong, Xiong Yuyan, Gajanayake Thusitha, Ming Xiu-Fen, Yang Zhihong (2012), p38 Mitogen-activated protein kinase is required for glucosamine-induced endothelial nitric oxide synthase uncoupling and plasminogen-activator inhibitor expression., in Circulation journal : official journal of the Japanese Circulation Society, 76(8), 2015-22.
Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis
Carvas Joao M., Vukolic Ana, Yepuri Gautham, Xiong Yuyan, Popp Katja, Schmutz Isabelle, Chappuis Sylvie, Albrecht Urs, Ming Xiu-Fen, Montani Jean-Pierre, Yang Zhihong (2012), Period2 gene mutant mice show compromised insulin-mediated endothelial nitric oxide release and altered glucose homeostasis, in FRONTIERS IN PHYSIOLOGY, 3(open), open-open.
Perspectives of targeting mTORC1–S6K1 in cardiovascular aging
Ming Xiu-Fen, Montani Jean-Pierre, Yang Zhihong (2012), Perspectives of targeting mTORC1–S6K1 in cardiovascular aging, in Frontier in Physiology, 3(5), Open-Open.
Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging.
Yepuri Gautham, Velagapudi Srividya, Xiong Yuyan, Rajapakse Angana G, Montani Jean-Pierre, Ming Xiu-Fen, Yang Zhihong (2012), Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging., in Aging cell, 11(6), 1005-16.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Research Day of Depart Med Frobourg Poster Role of p38mapk in vascular endothelial aging: Interaction witrh arginase-II and S6K1 signaling pathways 25.03.2015 Fribourg, Switzerland Yu Yi;
83rd Eur Athero Society Congress Talk given at a conference Arginase-II supresses endothelial autophagy and promotes smooth muscle cells apoptosis in atherosclerosis 22.03.2015 Glasgow, Great Britain and Northern Ireland Xiong Yuyan;
SCOPES Workshop Talk given at a conference Role of p38mapk in arginase-II-mediated eNOS-uncoupling and endothelial senescence 02.02.2015 Fribourg, Switzerland Yu Yi;
SCOPES Workshop Talk given at a conference Targeting arginase-II in age-associated cardiovascular and metabolic diseases 02.02.2015 Fribourg, Switzerland Yang Zhihong;
AGLA Cardiovsc & Metab Research Meeting Talk given at a conference p38mapk is involved in arginase-II induced eNOS-uncoupling in diet-induced obesity 22.01.2015 Fribourg, Switzerland Yu Yi;
AGLA-Cardiovasc & Metabolic Research Meeting 2015 Poster Long-term exposure of L-arginine accelerates endothelial cells senescence through Arg-II-S6K1 signaling 22.01.2015 Fribourg, Switzerland Xiong Yuyan;
International symposium on mechanisms of vasodilatation (MOVD) Poster Arginase-II promotes preadipocytes IL-6 production leading to endothelial inflammation 04.10.2014 Zürich, Switzerland Liu Chang;
International symposium on mechanisms of vasodilatation (MOVD) Poster Arginase-II induces endothelial senescence associated secretory phenotypes through p38mapk 04.10.2014 Zürich, Switzerland Yang Zhihong;
Swiss Physiology society annual meeting Poster Long-term exposure of L-arginine accelerates endothelial cells senescence through Arg-II-S6K1 signaling 09.09.2014 Fribourg, Switzerland Xiong Yuyan;
Swiss Physiology Annual meeting 2014 Talk given at a conference p38mapk is involved in arginase-II induced eNOS uncoupling in obesity 09.09.2014 Fribourg, Switzerland Yu Yi;
International symposium on mechanisms of vasodilatation (MOVD) Poster Arginase-II induces vascular SMC senescence and aopotosis through p66shc and p53 04.10.2013 Zürich, Switzerland Xiong Yuyan;
International symposium on mechanisms of vasodilatation (MOVD) Poster Arginase-II supresses endothelial autophagy through S6K1 and p53 independently of its L-arginine:ureahydrolase-activity 04.10.2013 Zürich, Switzerland Yu Yi;
Invited seminar Individual talk Arginase-II: The molecular interface connecting atherosclerosis, diabetes, and aging 19.03.2013 Zürich, Switzerland Yang Zhihong;
Department Research Day Talk given at a conference Targeting vascular disease signaling 11.05.2012 Fribourg, Switzerland Yang Zhihong;
Department Med. Seminar Individual talk Oxidative stress and inflammation: The common soil foraging, obesity, and atherosclerosis 24.04.2012 Fribourg, Switzerland Yang Zhihong;


Self-organised

Title Date Place
Cardiovascular & Metabolic Research Conference 2015, 4th Joint Meeting of the SSC working groups AGLA & CVBG 22.01.2015 Fribourg, Switzerland
Cardiovascular & Metabolic Research Conference 2014, 3rd Joint Meeting of the SSC working groups AGLA & CVBG 16.01.2014 Fribourg, Switzerland
AGLA Cardiovasc Biol meeting 10.01.2013 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Autophagie: Saubermachen in der Zelle University News of Fribourg International German-speaking Switzerland Western Switzerland 2015
Media relations: print media, online media The spirit is in the heart Zürich Heart House International 2015
Media relations: print media, online media Vascular investigations: Age and Arginase International Innovation International 2015
Media relations: print media, online media Interview: Arginase II Promotes Macrophage Inflammatory Responses Website of European Society of Cardiology, Working group “Atherosclerosis and Vascular Biology” International 2012

Awards

Title Year
Young Investigator Fellowship of 2015 Eur Athero Society (EAS) (EAS 2015 Fellowship) 2015
Faculty-Prize 2014 – Biology and Medicine, University of Fribourg 2014
Poster award at the meeting “3rd Research Day in Medicine”, May 21st , 2014 2014

Associated projects

Number Title Start Funding scheme
159582 Cell-specific pleiotropic effects of arginase-II on obesity-associated metabolic and vascular disorders 01.07.2015 Project funding
120435 The role of arginase II in atherogenesis, obesity and obesity-associated vascular dysfunctions 01.04.2008 Project funding
159582 Cell-specific pleiotropic effects of arginase-II on obesity-associated metabolic and vascular disorders 01.07.2015 Project funding
157658 High frequency, high resolution Ultrasound imaging platform (Vevo2100) for preclinical imaging 01.12.2014 R'EQUIP

Abstract

Background: Global population aging is accelerating, which will be accompanied with increase in age-associated diseases including cardiovascular disease in our society. Although aging has been proven to be a prominent independent risk factor for cardiovascular disease, the underlying mechanisms of cardiovascular aging have not been fully understood, yet. It has been well demonstrated that oxidative stress, i.e., enhanced production of reactive oxygen species (ROS) such as O2.- plays a critical role in endothelial aging. Among other sources of ROS, endothelial nitric oxide synthase (eNOS)-uncoupling appears to be an important mechanism of oxidative stress in endothelial aging, whereby eNOS generates large amount of O2.- instead the vasoprotective NO. Recent studies from others and our own showed that enhanced arginase activity (arginase-II in humans and mice) can cause endothelial dysfunction and also eNOS-uncoupling, which is generally believed (not proven) to be due to depletion of L-arginine for eNOS. However, a real absolute L-arginine deficiency does not exist either in cultured cells or in vivo, since L-arginine concentrations in culture medium or in plasma of animals or humans are more than sufficient (in mmol/L range) for eNOS. Suprisingly, chronic L-arginine supplementation paradoxically induces endothelial cell senescence. Patients with myocardial infarction or with peripheral artery disease who received L-arginine supplementation therapy for 6 months have higher mortality or shorter claudication working distance than placebo groups. These results do not support L-arginine deficiency theory on one hand and implicate on the other hand that L-arginine metabolites through Arg-II (urea, L-ornithine, polyamines) may promote endothelial dysfunction or eNOS-uncoupling. It is well established that genetic, dietary, and pharmacological inhibition of mTOR/S6K1 signalling extends lifespan in model organisms. Our recent study provides the first evidence for the causative role of hyperactive S6K1 activity in endothelial aging and eNOS-uncoupling in vitro and in vivo animal model. It is, however, not known, how S6K1 causes eNOS-uncoupling and acelerates endothelial aging. Our additional ongoing experiments demonstrate that S6K1 enhances Arg-II protein expression and activity in cultured human endothelial cells. Based on these results, we would like to investigate the hypothesis below Working hypothesis: S6K1 causes endothelial aging partly through Arg-II. The follwoing major specific questions will be addressed: Specific aims: (1) Does Arg-II promote endothelial cell senescence in culture through eNOS-uncoupling? (2) Does Arg-II promote eNOS-uncoupling and senescence through L-arginine deficiency or through its metabolites catalyzed through Arg-II such as urea, L-ornithine, or polyamines? (3) Does S6K1 induce endothelial senescence through activating Arg-II and what are the underlying molecular mechanisms: up-regulation of mRNA or protein translation or protein posttranslational modification? (4) Does Arg-II knock-out in mouse delay endothelial aging and extends lifespan? (5) Does S6K1 deficiency suppress aging-associated vascular Arg-II up-regulation/activation and endothelial dysfunction/senescence?Experimental design and/or methods: These specific questions will be addressed in two aging models i.e. in vitro senescence model with cultured human endothelial cells and in vivo aging models with mice deficient in Arg-II gene (Arg-II-/-) and S6K1 gene (S6K1-/-). Integrative approaches ranging from genetic, molecular/cellular, organ, and systemic analyses will be utilized. The significance of the project: This project will explore the causal role of S6K1 and Arg-II, the predominant isoform of arginase in human endothelial cells, in acceleration of vascular aging in vitro cultured endothelial cells and in vivo aging animal models. Particularly, the mechanisms of “L-arginine paradox” in relation to eNOS-uncoupling induced by Arg-II will be characterized, i.e. the functions of L-arginine metabolites through Arg-II in eNOS-uncoupling and endothelial senescence will be for the first time investigated. Furthermore, a novel function of S6K1 in regulation of Arg-II gene expression and/or enzymatic activity as well as the underlying molecular mechanisms in context of endothelial aging and dysfunction will be deeply explored. Expected results shall also justify therapeutic rationales of targeting S6K1 and Arg-II for aging-associated vascular disease and beyond, since eNOS-uncoupling, increased S6K1 and enhanced Arg-II activity are also observed under various pathological conditions such as atherosclerosis and obesity. Finally, the aspect of lifespan regulation by Arg-II will also be explored.
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