Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension

Gilinsky, M. A.; Polityko, Yulia K.; Al, Markel'; Latysheva, T. V.; Samson, Abraham O.; Polis, Baruh; Naumenko, S. E.

doi:10.1155/2020/4935386

Cited by 15 publications

(5 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we tested norvaline in mice at a dose of 50 mg/kg and found no indications of toxicity [43,86]. Other groups applied norvaline in rats and did not report toxic effects [87,88]. In this study, we treated zebrafish with substantially higher doses and again assessed its toxicity.…”

Section: Discussionmentioning

confidence: 80%

Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism

Banerjee

Khrystoforova

Polis

et al. 2021

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Living organisms repeatedly encounter stressful events and apply various strategies to survive. Polyamines are omnipresent bioactive molecules with multiple functions. Their transient synthesis, inducible by numerous stressful stimuli, is termed the polyamine stress response. Animals developed evolutionarily conserved strategies to cope with stresses. The urea cycle is an ancient attribute that deals with ammonia excess in terrestrial species. Remarkably, most fish retain the urea cycle genes fully expressed during the early stages of development and silenced in adult animals. Environmental challenges instigate urea synthesis in fish despite substantial energetic costs, which poses the question of the urea cycle's evolutionary significance. Arginase plays a critical role in oxidative stress-dependent reactions being the final urea cycle enzyme. Its unique subcellular localization, high inducibility, and several regulation levels provide a supreme ability to control the polyamine synthesis rate. Notably, oxidative stress instigates the arginase-1 activity in mammals. Arginase is also dysregulated in aging organisms' brain and muscle tissues, indicating its role in the pathogenesis of age-associated diseases. We designed a study to investigate the levels of the urea cycle and polyamine synthesis-related enzymes in a fish model of acute hypoxia. We evidence synchronized elevation of arginase-2 and ornithine decarboxylase following oxidative stress in adult fish and aging animals signifying the specific function of arginase-2 in fish. Moreover, we demonstrate oxidative stress-associated polyamine synthesis' induction and urea cycle' arrest in adult fish. The subcellular arginase localization found in the fish seems to correspond to its possible evolutionary roles.

show abstract

Section: Discussionmentioning

confidence: 80%

Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism

Banerjee

Khrystoforova

Polis

et al. 2021

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It has also been shown that blockers of Ar activity decreased the progression of Alzheimer's disease and improve cognition and memory in animal models ( Polis et al, 2018 ). In this study, we compared the effects of Norv a potent Ar inhibitor with well documented biological properties ( Gilinsky et al, 2020 ) and whose consumption is promoted in certain sports supplements. However, Norv consumption has been linked to toxic effects as per in vitro studies.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Of importance, the age-associated upregulation of arginase has been suggested to be involved in various pathologies. Endothelial dysfunction [ 143 ], hypertension [ 144 ], and diabetes mellitus [ 145 ] are among them.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension

Cited by 15 publications

References 68 publications

Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism

Acute hypoxia elevates arginase 2 and induces polyamine stress response in zebrafish via evolutionarily conserved mechanism

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

Alzheimer’s disease as a chronic maladaptive polyamine stress response

Contact Info

Product

Resources

About