Age-Dependent Oxidative Stress Elevates Arginase 1 and Uncoupled Nitric Oxide Synthesis in Skeletal Muscle of Aged Mice

Pandya, Chirayukumar D; Lee, Byung Moo; Toque, Haroldo A.; Mendhe, Bharati; Bragg, Robert; Pandya, Bhaumik A.; Atawia, Reem T.; Isales, Carlos M.; Hamrick, Mark W.; Caldwell, Robert W.; Fulzele, Sadanand

doi:10.1155/2019/1704650

Cited by 26 publications

(15 citation statements)

References 51 publications

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“…Increased arginase activity may be the result of mild, sustained oxidative stress in βThal + traits, as observed in normal aging [ 51 ], and a compensatory defense mechanism against the NOS-associated oxidative/nitrosative stress. In either case, it may contribute to the resistance of βThal + RBCs to malaria infection, since the host arginine (intracellular and introduced by RBC amino acid transporters) is metabolized by the parasite to sustain its metabolic needs [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Proteome of Stored RBC Membrane and Vesicles from Heterozygous Beta Thalassemia Donors

Tzounakas

Anastasiadi

Dzieciątkowska

et al. 2021

IJMS

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Genetic characteristics of blood donors may impact the storability of blood products. Despite higher basal stress, red blood cells (RBCs) from eligible donors that are heterozygous for beta-thalassemia traits (βThal+) possess a differential nitrogen-related metabolism, and cope better with storage stress compared to the control. Nevertheless, not much is known about how storage impacts the proteome of membrane and extracellular vesicles (EVs) in βThal+. For this purpose, RBC units from twelve βThal+ donors were studied through proteomics, immunoblotting, electron microscopy, and functional ELISA assays, versus units from sex- and aged-matched controls. βThal+ RBCs exhibited less irreversible shape modifications. Their membrane proteome was characterized by different levels of structural, lipid raft, transport, chaperoning, redox, and enzyme components. The most prominent findings include the upregulation of myosin proteoforms, arginase-1, heat shock proteins, and protein kinases, but the downregulation of nitrogen-related transporters. The unique membrane proteome was also mirrored, in part, to that of βThal+ EVs. Network analysis revealed interesting connections of membrane vesiculation with storage and stress hemolysis, along with proteome control modulators of the RBC membrane. Our findings, which are in line with the mild but consistent oxidative stress these cells experience in vivo, provide insight into the physiology and aging of stored βThal+ RBCs.

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Section: Discussionmentioning

confidence: 99%

Proteome of Stored RBC Membrane and Vesicles from Heterozygous Beta Thalassemia Donors

Tzounakas

Anastasiadi

Dzieciątkowska

et al. 2021

IJMS

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“…Other studies using models of aging and CVD have shown that endothelial Ar competes for L-arginine reducing eNOS activity and therefore, decreasing NO bioavailability ( Pandya et al, 2019 ; Shin et al, 2012 ; Zhu et al, 2017 ). On the other hand, Ar inhibition improves endothelial function in elderly healthy subjects ( Mahdi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging

Garate‐Carrillo

Navarrete‐Yanez

Ortiz-Vilchis

et al. 2020

European Journal of Pharmacology

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Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (−)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 μM), Epi (1 μM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity.

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“…Surprisingly, Arg1 levels gradually increase in skeletal muscles of mice during aging [ 142 ], nevertheless, its upturn is not followed by elevation in polyamine levels. This phenomenon may reflect a compensatory mechanism, which in any case is inadequate to support the polyamine content in aged organism, and causes arginine deficiency, NOS and ADC substrate deprivation.…”

Section: Evolutionary Perspective On Aging and Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Polis

Karasik

Samson

2021

Aging

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Polyamines are nitrogen-rich polycationic ubiquitous bioactive molecules with diverse evolutionary-conserved functions. Their activity interferes with numerous genes' expression resulting in cell proliferation and signaling modulation. The intracellular levels of polyamines are precisely controlled by an evolutionary-conserved machinery. Their transient synthesis is induced by heat stress, radiation, and other traumatic stimuli in a process termed the polyamine stress response (PSR). Notably, polyamine levels decline gradually with age; and external supplementation improves lifespan in model organisms. This corresponds to cytoprotective and reactive oxygen species scavenging properties of polyamines. Paradoxically, age-associated neurodegenerative disorders are characterized by upsurge in polyamines levels, indicating polyamine pleiotropic, adaptive, and pathogenic roles. Specifically, arginase overactivation and arginine brain deprivation have been shown to play an important role in Alzheimer’s disease (AD) pathogenesis. Here, we assert that a universal short-term PSR associated with acute stimuli is beneficial for survival. However, it becomes detrimental and maladaptive following chronic noxious stimuli, especially in an aging organism. Furthermore, we regard cellular senescence as an adaptive response to stress and suggest that PSR plays a central role in age-related neurodegenerative diseases' pathogenesis. Our perspective on AD proposes an inclusive reassessment of the causal relationships between the classical hallmarks and clinical manifestation. Consequently, we offer a novel treatment strategy predicated upon this view and suggest fine-tuning of arginase activity with natural inhibitors to preclude or halt the development of AD-related dementia.

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Age-Dependent Oxidative Stress Elevates Arginase 1 and Uncoupled Nitric Oxide Synthesis in Skeletal Muscle of Aged Mice

Cited by 26 publications

References 51 publications

Proteome of Stored RBC Membrane and Vesicles from Heterozygous Beta Thalassemia Donors

Proteome of Stored RBC Membrane and Vesicles from Heterozygous Beta Thalassemia Donors

Arginase inhibition by (−)-Epicatechin reverses endothelial cell aging

Alzheimer’s disease as a chronic maladaptive polyamine stress response

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