While the extensive hunt for therapeutics combating Alzheimer's disease (AD) has fallen short of delivering effective treatments, breakthroughs towards understanding the disease mechanisms and identifying areas for future research have nevertheless been enabled. The majority of clinical trials with β- and γ-secretase modulators have been suspended from additional studies or terminated due to toxicity issues and health concerns. The lack of progress in developing innovative AD therapies has also prompted a resurgence of interest in more traditional symptomatic treatments with cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, as well as in the research of immune response modulators. Recently, evidence has emerged showing that inhibitors of arginine metabolism and in particular blockers of arginase, an enzyme that catalyzes the breakdown of L-arginine, could present an effective therapeutic candidate for halting the progression of AD and boosting cognition and memory. In this commentary, we present a brief overview of reports on arginase inhibitors in AD mouse models and discuss emerging advantages and areas for careful consideration on the road to clinical translation.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- arginasa antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Within human pulmonary artery, neurotrophin growth factors [NTs; e.g. brain-derived neurotrophic factor (BDNF)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been reported, but their functional role is incompletely understood. We tested the hypothesis that BDNF is produced by human pulmonary artery endothelial cells (PAECs). In the context of hypoxia as a risk factor for pulmonary hypertension, we examined the effect of hypoxia on BDNF secretion and consequent autocrine effects on pulmonary endothelium. Initial ELISA analysis of circulating BDNF in 30 healthy human volunteers showed that 72 h exposure to high altitude (~11,000 ft, alveolar PO2 = 100 mmHg) results in higher BDNF compared to samples taken at sea level. Separately, in human PAECs exposed for 24h to normoxia vs. hypoxia (1-3% O2), ELISA of extracellular media showed increased BDNF levels. Furthermore, quantitative PCR of PAECs showed 3-fold enhancement of BDNF gene transcription with hypoxia. In PAECs, BDNF induced NO production (measured using an NO-sensitive fluorescent dye DAF2-DA) that was significantly higher under hypoxic conditions, an effect also noted with the TrkB agonist 7,8-DHF. Importantly, hypoxia-induced NO was blunted by neutralization of secreted BDNF using the chimeric TrkB-Fc. Both hypoxia and BDNF increased iNOS (but not eNOS) mRNA expression. In accordance, BDNF enhancement of NO in hypoxia was not blunted by 50 nM L-NAME (eNOS inhibition) but substantially lower with 100 μM L-NAME (eNOS and iNOS inhibition). Hypoxia and BDNF also induced expression of hypoxia inducible factor 1 alpha (HIF-1α), a subunit of the transcription factor HIF-1, and pharmacological inhibition of HIF-1 diminished hypoxia effects on BDNF expression and secretion, and NO production. These results indicate that human PAECs express and secrete BDNF in response to hypoxia via a HIF-1-regulated pathway.
- MeSH
- arginasa metabolismus MeSH
- arteria pulmonalis patologie MeSH
- cévní endotel patologie MeSH
- endoteliální buňky metabolismus sekrece MeSH
- exprese genu MeSH
- faktor 1 indukovatelný hypoxií metabolismus MeSH
- hypoxie buňky MeSH
- hypoxie krev MeSH
- kultivované buňky MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- mozkový neurotrofický faktor krev genetika sekrece MeSH
- oxid dusnatý metabolismus MeSH
- proteinkinasy metabolismus MeSH
- signální transdukce MeSH
- synthasa oxidu dusnatého, typ II metabolismus MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Endothelial dysfunction characterized by decreased nitric oxide (NO) bioavailability is the first stage of coronary artery disease. It is known that one of the factors associated with an increased risk of coronary artery disease is a high plasma level of uric acid. However, causative associations between hyperuricaemia and cardiovascular risk have not been definitely proved. In this work, we tested the effect of uric acid on endothelial NO bioavailability. Electrochemical measurement of NO production in acetylcholine-stimulated human umbilical endothelial cells (HUVECs) revealed that uric acid markedly decreases NO release. This finding was confirmed by organ bath experiments on mouse aortic segments. Uric acid dose-dependently reduced endothelium-dependent vasorelaxation. To reveal the mechanism of decreasing NO bioavailability we tested the effect of uric acid on reactive oxygen species production by HUVECs, on arginase activity, and on acetylcholine-induced endothelial NO synthase phosphorylation. It was found that uric acid increases arginase activity and reduces endothelial NO synthase phosphorylation. Interestingly, uric acid significantly increased intracellular superoxide formation. In conclusion, uric acid decreases NO bioavailability by means of multiple mechanisms. This finding supports the idea of a causal association between hyperuricaemia and cardiovascular risk.
- MeSH
- acetylcholin farmakologie MeSH
- arginasa metabolismus MeSH
- buněčné linie MeSH
- cévní endotel metabolismus MeSH
- down regulace MeSH
- endoteliální buňky pupečníkové žíly (lidské) MeSH
- fosforylace MeSH
- hyperurikemie metabolismus MeSH
- kyselina močová krev chemie metabolismus MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nemoci koronárních tepen metabolismus MeSH
- oxid dusnatý biosyntéza metabolismus MeSH
- reaktivní formy kyslíku chemie metabolismus MeSH
- superoxidy metabolismus MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antihistaminika metabolismus MeSH
- arginasa antagonisté a inhibitory metabolismus MeSH
- krysa rodu rattus MeSH
- modely u zvířat MeSH
- myši MeSH
- oxid dusnatý metabolismus MeSH
- receptory histaminu H1 MeSH
- thapsigargin farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
BACKGROUND: Production of nitric oxide (NO) by graft infiltrating macrophages has been proposed as an important effector mechanism of allograft rejection. Although high levels of NO are generated during allograft rejection, undetectable or only limited amounts of NO were found in rejected skin xenografts. METHODS: BALB/c mice were grafted with skin transplants from syngeneic, allogeneic or xenogeneic (rat) donors. The production of NO, cytokines and arginase in the grafts was determined by spectrophotometry, enzyme-linked immunosorbent assay, or polymerase chain reaction. Effects of depletion of CD4+ cells, neutralization of interleukin (IL)-4 or application of arginase inhibitors N(omega)-hydroxy-L-arginine (L-NOHA) and L-valine on production of NO in rejected xenografts were evaluated. RESULTS: Rejection of rat skin xenografts, on the contrary to rejection of allografts, was associated with a local high production of Th2 cytokines IL-4 and IL-10, overexpression of arginase genes, strongly enhanced arginase activity and attenuated NO generation in the graft. The supernatants obtained after cultivation of skin xenograft (but not allograft or syngeneic graft) explants contained a high arginase activity and strongly suppressed NO production by activated macrophages. This suppression was completely inhibited by L-NOHA or was overcome by an excess of exogenous L-arginine, a substrate for NO synthesis. Cocultivation of xenograft explants that did not produce NO with arginase inhibitors L-NOHA or L-valine restored NO generation in the graft. CONCLUSION: The results suggest that upregulation of arginase activity by Th2 cytokines during xenograft rejection limits the bioavailability of L-arginine for the inducible NO synthase and thus attenuates generation of NO by the graft-infiltrating macrophages.
- MeSH
- arginasa antagonisté a inhibitory genetika metabolismus MeSH
- arginin metabolismus MeSH
- financování organizované MeSH
- homologní transplantace MeSH
- interleukin-10 biosyntéza MeSH
- interleukin-4 biosyntéza MeSH
- krysa rodu rattus MeSH
- kůže metabolismus sekrece MeSH
- makrofágy metabolismus sekrece MeSH
- myši MeSH
- oxid dusnatý biosyntéza MeSH
- regulace genové exprese enzymů MeSH
- rejekce štěpu enzymologie imunologie metabolismus MeSH
- techniky tkáňových kultur MeSH
- Th1 buňky imunologie MeSH
- Th2 buňky imunologie MeSH
- transplantace heterologní MeSH
- transplantace kůže MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- MeSH
- arginasa farmakokinetika metabolismus MeSH
- bronchiální hyperreaktivita etiologie patofyziologie MeSH
- finanční podpora výzkumu jako téma MeSH
- morčata anatomie a histologie fyziologie MeSH
- NG-nitroargininmethylester metabolismus MeSH
- ovalbumin fyziologie škodlivé účinky MeSH
- synthasa oxidu dusnatého biosyntéza MeSH
- zvířata MeSH
- Check Tag
- morčata anatomie a histologie fyziologie MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- aminokyseliny metabolismus MeSH
- arginasa metabolismus MeSH
- arginin analogy a deriváty chemie MeSH
- cévní endotel účinky léků MeSH
- cévní rezistence účinky léků MeSH
- lidé MeSH
- oxid dusnatý biosyntéza chemie MeSH
- synthasa oxidu dusnatého chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
