Arginase-II Deficiency Extends Lifespan in Mice

Xiong, Yuyan; Yepuri, Gautham; Montani, Jean‐Pierre; Ming, Xiu‐Fen; Yang, Zhihong

doi:10.3389/fphys.2017.00682

Cited by 36 publications

(28 citation statements)

References 40 publications

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“…A major contribution of its activity in determining microvascular dysfunction and remodeling has been outlined in obesity (Chung et al, 2014;Masi et al, 2018), arterial hypertension (Michell et al, 2011), and T2DM (Shemyakin et al, 2012). Interestingly, knockout of the gene encoding for the mitochondrial arginase type II (Arg-II) has been shown to restore eNOS function, to counteract the SASP in senescent ECs (Wu et al, 2015), and to extend lifespan in mice through the inhibition of mTOR signaling (Xiong et al, 2017). Moreover, mTOR blockade with rapamycin decreases the expression of the arterial senescence marker p19 and ameliorates oxidative stress-mediated endothelial dysfunction in old mice, suggesting a possible role for the rapamycin analogs, i.e., rapalogs, in the treatment of age-related CVDs (Lesniewski et al, 2017).…”

Section: Therapeutic Interventions Targeting Endothelial Cell Metabolismmentioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

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Section: Therapeutic Interventions Targeting Endothelial Cell Metabolismmentioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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“…So, it was suggested that ARGII and mTOR-S6K1 pathways play an important role in promoting oxidative stress, inflammation, senescence and death, which eventually leads to metabolic disorders (X.-F. 2013). Therefore, targeting ARGII was recently proposed as a means of decelerating age-related diseases treatment (Xiong et al 2017).…”

Section: Introductionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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“…A set of the histochemical investigations revealed a significant reduction of ARG1 immunopositivity in the liver and ARG2 immunopositivity in the kidney following the treatment. Worth mentioning that ARG2 deficiency extends the lifespan of mice (Xiong et al, 2017). Moreover, targeting ARG2 protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation (Liu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

Polis

Srikanth

Gurevich

et al. 2018

Preprint

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Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder with an insidious onset. The disease is characterized by cognitive impairment and a distinct pathology with neuritic plaques and neurofibrillary tangles.Growing evidence highlights the role of arginase activity in the manifestation of AD.Upregulation of arginase was shown to contribute to endothelial dysfunction, atherosclerosis, diabetes, and neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target.Here, we administer an arginase inhibitor L-norvaline to a mouse model of AD. Then, we evaluate the neuroprotective effect of L-norvaline using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identify the biological pathways activated by the treatment.Remarkably, we find that L-norvaline treatment reverses the cognitive decline in AD mice. We show the treatment is neuroprotective as indicated by reduced betaamyloidosis, alleviated microgliosis, and TNFα transcription levels. Moreover, elevated levels of neuroplasticity related protein PSD-95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclose several biological pathways, which are involved in cell survival and neuroplasticity and are activated by the treatment.Through these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interfere with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders.

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Arginase-II Deficiency Extends Lifespan in Mice

Cited by 36 publications

References 40 publications

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Where Metabolism Meets Senescence: Focus on Endothelial Cells

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

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