RESUMO
Herein, we describe the rational design, synthesis and in vitro functional characterization of new heme-dependent, direct soluble guanylyl cyclase (sGC) agonists. These new compounds bear a 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton, modified to enable efficient sGC binding and stimulation. To gain insights into structure-activity relationships, the N6-alkylation of the skeleton was explored, while a pyrimidine ring, substituted with various C5'-polar groups, was installed at position C3. Among the newly synthesized 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones, derivatives 14b, 15b and 16a display characteristic features of sGC "stimulators" in A7r5 vascular smooth muscle cells in vitro. They strongly synergize with the NO donor, sodium nitroprusside (SNP) in inducing cGMP generation in a manner that requires the presence of a reduced heme moiety associated with sGC, and elevate the cGMP-responsive phosphorylation of the protein VASP at Ser239. In line with their sGC stimulating capacity, docking calculations of derivatives 16a, 15(a-c) on a cryo-EM structure of human sGC (hsGC) in an ΝΟ-activated state indicated the implication of 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton in efficient bonding interactions with the recently identified region that binds known sGC stimulators, while the presence of either a N6-H or N6-methyl group pointed to enhanced binding affinity. Moreover, the in vitro functional effects of our newly identified sGC stimulators were compatible with a beneficial role in vascular homeostasis. Specifically, derivative 14b reduced A7r5 cell proliferation, while 16a dampened the expression of adhesion molecules ICAM-1 and P/E-Selectin in Human Umbilical Vein Endothelial Cells (HUVECs), as well as the subsequent adhesion of U937 leukocytes to the HUVECs, triggered by tumor necrosis factor alpha (TNF-α) or interleukin-1 beta (IL-1ß). The fact that these compounds elevate cGMP only in the presence of NO may indicate a novel way of interaction with the enzyme and may make them less prone than other direct sGC agonists to induce characteristic hypotension in vivo.
Assuntos
Células Endoteliais , Guanilato Ciclase , Humanos , Células Endoteliais/metabolismo , Ativação Enzimática , Guanilato Ciclase/metabolismo , Heme , Óxido Nítrico/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores , AlquilaçãoRESUMO
Several proteases are involved in the proteolytic processing of the amyloid precursor protein (APP) generating the amyloidogenic Aß peptide, which can act as the triggering pathological effector of Alzheimer's disease (AD). Among these proteases, the ß-site amyloid precursor protein cleaving enzyme 2 (BACE2) is of particular interest because it was first proposed as an alternative ß-secretase to its homolog BACE1; however, accumulating evidence suggests that BACE2 acts as a non-amyloidogenic α-secretase and exerts neuroprotective effects. In this issue of J Neurochem, Katusic et al. present an interesting article reporting that BACE2 plays a role in preservation of cerebral vascular endothelial nitric oxide synthase (eNOS) function, thus exerting protective functions. Their data support that the process is mediated by the large soluble non-amyloidogenic APP fragment sAPPα through the γ-aminobutyric acid type B receptor 1, which enhances the expression of a major transcription factor for eNOS gene expression in endothelial cells, the Krüppel-like factor 2. These protective functions of BACE2 contrast with the pathogenic role of BACE1 as a key player in the AD amyloidogenic pathway. Indeed, many efforts have been invested in BACE1 inhibitors as potential disease modifiers for AD. Unfortunately, the results in clinical trials have been disappointing. In this scenario, a better understanding of the functions of BACE2, as well as the selectivity of BACE1 inhibitors with respect to other ß-secretases (mainly BACE2), is crucial for the development of new therapeutic agents. Furthermore, specific cellular targeting should also be considered to improve such therapies due to the diverse balance of secretases targeting APP and the complex cross-talk between them and the generated APP fragments.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Humanos , Precursor de Proteína beta-Amiloide , Células Endoteliais , Ácido Aspártico Endopeptidases , EndotélioRESUMO
Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness worldwide. DR was recently defined as a neurovascular disease associated with tissue-specific neurovascular impairment of the retina in patients with diabetes. Neurovascular cell death is the main cause of neurovascular impairment in DR. Thus, neurovascular cell protection is a potential therapy for preventing the progression of DR. Growing evidence indicates that a variety of cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis, are associated with neurovascular cell death in DR. These forms of regulated cell death may serve as therapeutic targets for ameliorating the pathogenesis of DR. This review focuses on these cell death mechanisms and describes potential therapies for the treatment of DR that protect against neurovascular cell death.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Humanos , Morte Celular , Apoptose , Retina , PiroptoseRESUMO
Vascular endothelial dysfunction and platelet activation play a key role in tumor metastasis, and therefore, both of these processes are considered important therapeutic targets in cancer. The aim of our studies was to analyze antimetastatic activity of combination therapy using nitric oxide donor DETA/NO and antiplatelet drug clopidogrel. Nitric oxide acts as a vasoprotective mediator, while clopidogrel inhibits ADP-mediated platelet aggregation. 4T1-luc2-tdTomato cell line transplanted intravenously (i.v.) and 4T1 cell line transplanted orthotopically were used as metastatic mammary gland cancer models. Moreover, antiaggregation action of compounds was tested ex vivo on the blood samples taken from breast cancer patients. We have shown that in selected dosage regimes, DETA/NO combined with clopidogrel significantly reduced lung metastatic foci formation in an i.v. model, and such inhibition was transiently observed also in an orthotopic model. The antimetastatic effect was correlated with a significant increase of prostacyclin (PGI2) metabolite and reduction of endothelin-1, sE-selectin, sI-CAM, and TGF-ß plasma levels as well as decreased V-CAM expression on the endothelium. Combination therapy decreased fibrinogen binding to the resting platelets at the early stage of tumor progression (day 14). However, at the later stages (days 21 and 28), the markers of platelet activation were detected (increased JON/A antibody bound, P-selectin level, binding of fibrinogen, and vWf). Decreased aggregation as well as a lower release of TGF-ß were detected in platelets incubated ex vivo with compounds tested from metastatic breast cancer patients. Although combination therapy increases E-cadherin, the increase of N-cadherin and α-SMA in tumor tissue was also observed. The results showed that at the early stages of tumor progression, combined therapy with DETA/NO and clopidogrel improves vasoprotective and antiplatelet activity. However, in advanced tumors, some adverse effects toward platelet activation can be observed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Doadores de Óxido Nítrico/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Animais , Neoplasias da Mama/sangue , Linhagem Celular Tumoral/transplante , Clopidogrel/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , Humanos , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Ativação Plaquetária/efeitos dos fármacos , Plasma Rico em Plaquetas/efeitos dos fármacos , Triazenos/administração & dosagemRESUMO
Nitric oxide (NO) plays a pivotal role in the maintenance of cardiovascular homeostasis. A reduction in the bioavailability of endogenous NO, manifest as a decrease in the production and/or impaired signaling, is associated with many cardiovascular diseases including hypertension, atherosclerosis, stroke and heart failure. There is substantial evidence that reactive oxygen species (ROS), generated predominantly from NADPH oxidases (Nox), are responsible for the reduced NO bioavailability in vascular and cardiac pathologies. ROS can compromise NO function via a direct inactivation of NO, together with a reduction in NO synthesis and oxidation of its receptor, soluble guanylyl cyclase. Whilst nitrovasodilators are administered to compensate for the ROS-mediated loss in NO bioactivity, their clinical utility is limited due to the development of tolerance and resistance and systemic hypotension. Moreover, efforts to directly scavenge ROS with antioxidants has had limited clinical efficacy. This review outlines the therapeutic utility of NO-based therapeutics in cardiovascular diseases and describes the source and impact of ROS in these pathologies, with particular focus on the interaction with NO. Future therapeutic approaches in the treatment of cardiovascular diseases are highlighted with a focus on nitroxyl (HNO) donors as an alternative to traditional NO donors and the development of novel Nox inhibitors.
Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Homeostase/fisiologia , Humanos , Doadores de Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
By using two structurally unrelated hydrogen sulfide (H2 S) donors 5-(4-methoxyphenyl) -3H-1, 2-dithiole-3-thione (ADT) and sodium hydrosulfide (NaHS), this study investigated if H2 S protected blood-brain barrier (BBB) integrity following middle cerebral artery occlusion (MCAO). ICR mice underwent MCAO and received H2 S donors at 3 h after reperfusion. Infarction, neurological scores, brain edema, Evans blue (EB) extravasation, and tight junction protein expression were examined at 48 h after MCAO. We also investigated if ADT protected BBB integrity by suppressing post-ischemic inflammation-induced Matrix Metalloproteimase-9 (MMP9) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). ADT increased blood H2 S concentrations, decreased infarction, and improved neurological deficits. Particularly, ADT reduced EB extravasation, brain edema and preserved expression of tight junction proteins in the ischemic brain. NaHS also increased blood H2 S levels and reduced EB extravasation following MCAO. Moreover, ADT inhibited expression of pro-inflammatory markers induced Nitric Oxide Synthase (iNOS) and IL-1ß while enhanced expression of anti-inflammatory markers arginase 1 and IL-10 in the ischemic brain. Accordingly, ADT attenuated ischemia-induced expression and activity of MMP9. Moreover, ADT reduced NOX-4 mRNA expression, NOX activity, and inhibited nuclear translocation of Nuclear Factor Kappa-B (NF-κB) in the ischemic brain. In conclusion, H2 S donors protected BBB integrity following experimental stroke possibly by acting through NF-κB inhibition to suppress neuroinflammation induction of MMP9 and NOX4-derived free radicals. To determine H2 S effects on blood-brain barrier (BBB) disruption following stroke, we used two structurally unrelated H2 S donors ADT and NaHS. Both ADT and NaHS remarkably protected BBB integrity following experimental stroke. The slow-releasing donor ADT also reduced post-ischemic inflammation-induced expression and activity of MMP9 and NOX4 in the ischemic brain possibly by inhibiting NF-κB activation.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Sulfeto de Hidrogênio/farmacologia , Fármacos Neuroprotetores , Tionas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Edema Encefálico/patologia , Corantes , Ensaio de Imunoadsorção Enzimática , Azul Evans , Sulfeto de Hidrogênio/sangue , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/prevenção & controle , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Peroxidase/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Phylloquinon (PK) and menaquinones (MK) are both naturally occurring compounds belonging to vitamin K group. Present study aimed to comprehensively analyze the influence of PK in several models of vascular dysfunction to determine whether PK has vasoprotective properties, similar to those previously described for MK. Effects of PK and MK on endothelial dysfunction were studied in ApoE/LDLR-/- mice in vivo, in the isolated aorta incubated with TNF, and in vascular cells as regard inflammation and cell senescence (including replicative and stress-induced models of senescence). Moreover, the vascular conversion of exogenous vitamins to endogenous MK-4 was analyzed. PK, as well as MK, given for 8 weeks in diet (10 mg/kg) resulted in comparable improvement in endothelial function in the ApoE/LDLR-/- mice. Similarly, PK and MK prevented TNF-induced impairment of endothelium-dependent vasorelaxation in the isolated aorta. In in vitro studies in endothelial and vascular smooth muscle cells, we identified that both PK and MK displayed anti-senescence effects via decreasing DNA damage while in endothelial cells anti-inflammatory activity was ascribed to the modulation of NFκB activation. The activity of PK and MK was comparable in terms of their effect on senescence and inflammation. Presence of endogenous synthesis of MK-4 from PK in aorta and endothelial and smooth muscle cells suggests a possible involvement of MK in vascular effects of PK. In conclusion, PK and MK display comparable vasoprotective effects, which may be ascribed, at least in part, to the inhibition of cell senescence and inflammation. The vasoprotective effect of PK in the vessel wall can be related to the direct effects of PK, as well as to the action of MK formed from PK in the vascular wall.
Assuntos
Senescência Celular , Endotélio Vascular , Vitamina K 1 , Animais , Senescência Celular/efeitos dos fármacos , Camundongos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Vitamina K 1/farmacologia , Vitamina K 2/farmacologia , Vitamina K 2/análogos & derivados , Masculino , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Vasodilatação/efeitos dos fármacos , Camundongos Knockout , Aorta/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
The aim of the present study was to investigate the effects of vascular tissue levels of l-carnitine and its precursor, γ-butyrobetaine (GBB), on the development of endothelial dysfunction induced by 5 µmol/L lysophosphatidylcholine (LPC), 10 mmol/L triglycerides (TG) or a high glucose concentration (44 mmol/L). Changes in vascular tissue levels of l-carnitine and GBB were induced by administration of l-carnitine (100 mg/kg), mildronate (100 mg/kg; an inhibitor of l-carnitine synthesis) or their combination to male Wistar rats for 2 weeks. Treatment with l-carnitine elevated vascular tissue levels of l-carnitine, whereas administration of mildronate reduced l-carnitine levels and increased GBB levels. Experimental animals that received the combination of both drugs showed elevated tissue levels of GBB. The results from organ bath experiments demonstrated that increased GBB levels with preserved l-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by high glucose. However, changes in vascular tissue l-carnitine and GBB levels had no impact on endothelial dysfunction induced by TG or LPC. The results demonstrate that increased levels of GBB with preserved l-carnitine content in vascular tissue attenuate the development of endothelial dysfunction induced by high glucose concentrations.
Assuntos
Betaína/análogos & derivados , Carnitina/metabolismo , Carnitina/farmacologia , Endotélio Vascular/metabolismo , Glucose/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Betaína/metabolismo , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/farmacologia , Carnitina/administração & dosagem , Quimioterapia Combinada , Glucose/administração & dosagem , Masculino , Metilidrazinas/administração & dosagem , Metilidrazinas/farmacologia , Ratos , Ratos WistarRESUMO
We aimed to investigate serum amino-terminal C-type natriuretic peptide (NT-proCNP) and its relationship with quantitative and qualitative HDL-parameters in patients with end-stage renal disease (ESRD) before, then 1 and 6 months after kidney transplantation (TX). Seventy patients (47 males, 23 females, mean age 51.7 ± 12.4 years) were enrolled in a prospective follow-up study. We examined serum creatinine, C-reactive protein, procalcitonin, fasting glucose and lipid parameters before, then 1 and 6 months after TX. High-density lipoprotein- (HDL)-associated paraoxonase-1 (PON1) paraoxonase and arylesterase activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. NT-proCNP and oxidized low-density lipoprotein (oxLDL) levels were measured by ELISA. Mean NT-proCNP was 45.8 ± 21.9 pmol/L before renal transplantation and decreased markedly 1 month and 6 months after transplantation (5.3 ± 2.5 and 7.7 ± 4.9 pmol/L, respectively, P = 1 × 10-4). During the 6 months' follow-up, PON1 arylesterase, paraoxonase and salt-stimulated paraoxonase activities improved. NT-proCNP positively correlated with procalcitonin and creatinine and negatively with GFR, LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C). There was a negative correlation between serum NT-proCNP and PON1 arylesterase activity. According to the multiple regression analysis, the best predicting variables of NT-proCNP were serum procalcitonin, creatinine and PON1 arylesterase activity. NT-proCNP might be a novel link between HDL dysfunction and impaired vascular function in ESRD, but not after kidney transplantation. Further studies in larger populations are needed to clarify the exact role of NT-proCNP in the risk prediction for cardiovascular comorbidities and complications in ESRD.
Assuntos
Falência Renal Crônica , Transplante de Rim , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Peptídeo Natriurético Tipo C , Lipoproteínas HDL , Seguimentos , Estudos Prospectivos , Pró-Calcitonina , Arildialquilfosfatase/metabolismo , Creatinina , Falência Renal Crônica/cirurgia , Vasodilatadores , ColesterolRESUMO
Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01-2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01-0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.
RESUMO
Diabetic retinopathy has recently been defined as a highly specific neurovascular complication of diabetes. The chronic progression of the impairment of the interdependence of neurovascular units (NVUs) is associated with the pathogenesis of diabetic retinopathy. The NVUs consist of neurons, glial cells, and vascular cells, and the interdependent relationships between these cells are disturbed under diabetic conditions. Clinicians should understand and update the current knowledge of the neurovascular impairments in diabetic retinopathy. Above all, neuronal cell death is an irreversible change, and it is directly related to vision loss in patients with diabetic retinopathy. Thus, neuroprotective and vasoprotective therapies for diabetic retinopathy must be established. Understanding the physiological and pathological interdependence of the NVUs is helpful in establishing neuroprotective and vasoprotective therapies for diabetic retinopathy. This review focuses on the pathogenesis of the neurovascular impairments and introduces possible neurovascular protective therapies for diabetic retinopathy.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Retinopatia Diabética/terapia , Humanos , NeurôniosRESUMO
Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25mg/kg/day) was administered via oral gavage for 11days to Ang II (1.2mg/kg/day)-infused C57BL/6J mice (8-10weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1-10nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11days reverses the impaired endothelial function and with a marked inhibition of AT1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound.
Assuntos
Angiotensina II/toxicidade , Benzofuranos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Endotélio Vascular/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Resultado do TratamentoRESUMO
Hydrogen sulphide (H2S) is endogenously produced in vascular tissue and has anti-oxidant and vasoprotective properties. This study investigates whether chronic treatment using the fast H2S donor NaHS could elicit a vasoprotective effect in diabetes. Diabetes was induced in male C57BL6/J mice with streptozotocin (60 mg/kg daily, ip for 2 weeks) and confirmed by elevated blood glucose and glycated haemoglobin levels. Diabetic mice were then treated with NaHS (100 µmol/kg/day) for 4 weeks, and aortae collected for functional and biochemical analyses. In the diabetic group, both endothelium-dependent vasorelaxation and basal nitric oxide (NOâ¢) bioactivity were significantly reduced ( p < 0.05), and maximal vasorelaxation to the NO⢠donor sodium nitroprusside was impaired ( p < 0.05) in aorta compared to control mice. Vascular superoxide generation via nicotine adenine dinucleotide phosphate (NADPH) oxidase ( p < 0.05) was elevated in aorta from diabetic mice which was associated with increased expression of NOX2 ( p < 0.05). NaHS treatment of diabetic mice restored endothelial function and exogenous NO⢠efficacy back to control levels. NaHS treatment also reduced the diabetes-induced increase in NADPH oxidase activity, but did not affect NOX2 protein expression. These data show that chronic NaHS treatment reverses diabetes-induced vascular dysfunction by restoring NO⢠efficacy and reducing superoxide production in the mouse aorta.
Assuntos
Antioxidantes/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfetos/administração & dosagem , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hemoglobinas Glicadas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , NADPH Oxidase 2/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Superóxidos/metabolismo , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein that belongs to the tumour necrosis factor (TNF) cytokine superfamily. TRAIL is expressed by numerous cell types including vascular cells, immune cells and adipocytes. Although originally thought to induce apoptosis in malignant or transformed cells only, it is now known that TRAIL can bind up to 5 distinct receptors to activate complex signalling pathways, and is capable of exerting pleiotropic effects in non-transformed cells. In this respect, a number of clinical and animal studies point to the potential vasoprotective influence of TRAIL, with TRAIL deficiency being linked to accelerated atherosclerosis and vascular calcification. Moreover, exogenous TRAIL administration has been shown to exhibit anti-atherosclerotic activity in-vivo. In-vitro studies on TRAIL in this context have yielded conflicting results however, with evidence of both pro-atherogenic and vasoprotective effects ascribed to TRAIL. Notwithstanding these various studies, mechanistic information on the precise nature of TRAIL-mediated injury/protection within the vasculature, as well as the identity of the downstream molecular/cellular targets of TRAIL, is still quite limited. In this review, we will summarize our current knowledge of TRAIL regulation, signalling mechanisms, and its apparent involvement in CVD pathogenesis as a prelude to examining the existing evidence for TRAIL-mediated vasoprotection. To this end, extensive in vitro, in vivo, and clinical studies will be reviewed and critical findings highlighted.
Assuntos
Aterosclerose/patologia , Vasos Sanguíneos/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Humanos , Fatores de Proteção , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologiaRESUMO
UNLABELLED: : Spinal cord injury (SCI) is a life-threatening condition with multifaceted complications and limited treatment options. In SCI, the initial physical trauma is closely followed by a series of secondary events, including inflammation and blood spinal cord barrier (BSCB) disruption, which further exacerbate injury. This secondary pathology is partially mediated by the systemic immune response to trauma, in which cytokine production leads to the recruitment/activation of inflammatory cells. Because early intravenous delivery of mesenchymal stromal cells (MSCs) has been shown to mitigate inflammation in various models of neurologic disease, this study aimed to assess these effects in a rat model of SCI (C7-T1, 35-gram clip compression) using human brain-derived stromal cells. Quantitative polymerase chain reaction for a human-specific DNA sequence was used to assess cell biodistribution/clearance and confirmed that only a small proportion (approximately 0.001%-0.002%) of cells are delivered to the spinal cord, with the majority residing in the lung, liver, and spleen. Intriguingly, although cell populations drastically declined in all aforementioned organs, there remained a persistent population in the spleen at 7 days. Furthermore, the cell infusion significantly increased splenic and circulating levels of interleukin-10-a potent anti-inflammatory cytokine. Through this suppression of the systemic inflammatory response, the cells also reduced acute spinal cord BSCB permeability, hemorrhage, and lesion volume. These early effects further translated into enhanced functional recovery and tissue sparing 10 weeks after SCI. This work demonstrates an exciting therapeutic approach whereby a minimally invasive cell-transplantation procedure can effectively reduce secondary damage after SCI through systemic immunomodulation. SIGNIFICANCE: Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to being recognized as major players in neurotrauma, pericytes have been discovered to share a common origin and potentially function with traditionally defined mesenchymal stromal cells (MSCs). Although there have been several in vitro comparisons, the in vivo therapeutic application of human brain-derived stromal cells has not been previously evaluated. This study demonstrates that these cells not only display a MSC phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of great interest for therapeutic use in spinal cord injury.
Assuntos
Encéfalo/irrigação sanguínea , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Pericitos/transplante , Traumatismos da Medula Espinal/cirurgia , Medula Espinal/irrigação sanguínea , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Animais , Células Cultivadas , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Pericitos/imunologia , Pericitos/metabolismo , Fenótipo , Ratos Wistar , Fluxo Sanguíneo Regional , Medula Espinal/imunologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Baço/imunologia , Baço/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Fatores de Tempo , Cordão Umbilical/citologiaRESUMO
Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Transtornos Cerebrovasculares/prevenção & controle , Disfunção Cognitiva/prevenção & controle , Hipóxia , Animais , HumanosRESUMO
Obesity is strongly associated with the cause of structural and functional changes of the artery. Oxidative stress and inflammation play a critical role in the development of obesity-induced cardiovascular disorders. Our group previously found that an imidazopyridine derivative X22 showed excellent anti-inflammatory activity in LPS-stimulated macrophages. This study was designed to investigate the protective effects of X22 on high fat diet (HFD)-induced arterial injury and its underlying mechanisms. We observed that palmitate (PA) treatment in HUVECs induced a marked increase in reactive oxygen species, inflammation, apoptosis, and fibrosis. All of these changes were effectively suppressed by X22 treatment in a dose-dependent manner, associated with NF-κB inactivation and Nrf-2 activation. In HFD-fed rats, administration of X22 at 10mg/kg significantly decreased the arterial inflammation and oxidative stress, and eventually improved the arterial matrix remodeling and apoptosis. X22 at 10mg/kg showed a comparable bioactivity with the positive control, curcumin at 50mg/kg. The in vivo beneficial effects of X22 are also associated with its ability to increase Nrf2 expression and inhibit NF-κB activation in the artery of HFD-fed rats. Overall, these results suggest that X22 may have therapeutic potential in the treatment of obesity-induced artery injury via regulation of Nrf2-mediated oxidative stress and NF-κB-mediated inflammation.