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1.
Pregnancy Hypertens ; 24: 50-57, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33677419

RESUMO

Preeclampsia affects 5-8% of pregnancies and is characterized by hypertension, placental ischemia, neurological impairment, and an increase in circulating inflammatory cytokines, including Interleukin-17 (IL17). While placental ischemia has also been shown to impair cerebrovascular function, it is not known which placental-associated factor(s) drive this effect. The purpose of this study was to examine the effects of IL17 on cerebrovascular function during pregnancy. To achieve this goal, pregnant rats were infused with either IL17 (150 pg/day, 5 days, osmotic minipump), or vehicle (saline/0.7% BSA osmotic minipump) starting at gestational day (GD) 14. On GD 19, the cerebral blood flow (CBF) response to increases in mean arterial pressure (MAP) was measured in vivo, and myogenic constrictor responses of the middle cerebral artery (MCA) were assessed ex vivo. IL17 increased MAP but impaired CBF responses only at the highest arterial pressure measured (190 mmHg). Myogenic constrictor responses overall were mostly unaffected by IL17 infusion; however, the intraluminal pressure at which peak myogenic tone was generated was lower in the IL17 infused group (120 vs 165 mm Hg), suggesting maximal tone is exerted at lower intraluminal pressures in IL17-treated pregnant rats. Consistent with the lack of substantial change in overall myogenic responsiveness, there was no difference in cerebral vessel expression of putative mechanosensitive protein ßENaC, but a tendency towards a decrease in ASIC2 (p = 0.067) in IL17 rats. This study suggests that infusion of IL17 independent of other placental ischemia-associated factors is insufficient to recapitulate the features of impaired cerebrovascular function during placental ischemia. Further studies to examine of the role of other pro-inflammatory cytokines, individually or a combination, are necessary to determine mechanisms of cerebral vascular dysfunction during preeclampsia.


Assuntos
Circulação Cerebrovascular , Hipertensão/fisiopatologia , Interleucina-17/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Pré-Eclâmpsia/etiologia , Canais Iônicos Sensíveis a Ácido/metabolismo , Canais Iônicos Sensíveis a Ácido/farmacologia , Animais , Pressão Sanguínea , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Interleucina-17/metabolismo , Artéria Cerebral Média/metabolismo , Gravidez , Ratos Sprague-Dawley
2.
Pregnancy Hypertens ; 23: 11-17, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33161224

RESUMO

BACKGROUND: The flavonoid, luteolin, promotes vasorelaxation in various arteries through endothelial-dependent and independent mechanisms. Although there is growing interest in the vasoactive effects of flavonoids on maternal vascular function during pregnancy, it is unknown whether luteolin elicits vasorelaxation in the uterine circulation. We tested the hypothesis that luteolin induces vasorelaxation via endothelial-dependent mechanisms in uterine arteries from normal pregnant rats during late gestation. METHODS: Uterine arteries and aortas were isolated from Sprague-Dawley rats at gestational day 19 and prepared for wire myography. RESULTS: The potency of luteolin-induced vasorelaxation was examined between uterine arteries and the aortas. By 50 µM of luteolin, there was complete relaxation (100.5 ± 5.2%) in uterine arteries as compared to aortas (27.5 ± 10.0%). Even the highest concentration of 100 µM luteolin produced less than half relaxation (43.6 ± 8.6%) in aortas compared to uterine arteries. We then explored if luteolin-induced vasorelaxation in uterine arteries from pregnant rats was mediated by endothelial-dependent vasorelaxation pathways, including nitric oxide synthase (NOS), cyclooxygenase (COX), or potassium (K+) channels. Blocking these pathways with N(G)-Nitro-l-arginine methyl ester hydrochloride (L-NAME), indomethacin, or tetraethylammonium (TEA)/high potassium chloride (KCl), respectively, did not alter luteolin responses in uterine arteries from pregnant rats. These findings suggested that endothelial factors may not mediate luteolin-induced vasorelaxation in uterine arteries during pregnancy. Indeed, experiments where the endothelium was removed did not alter luteolin-induced vasorelaxation in uterine arteries during pregnancy. CONCLUSIONS: Luteolin directly promotes vasorelaxation in the medial smooth muscle layer of uterine arteries during normal pregnancy.


Assuntos
Luteolina/farmacologia , Artéria Uterina/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
3.
Hypertens Pregnancy ; 39(4): 451-460, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33119997

RESUMO

Introduction:Women with preeclampsia (PE) and reduced uterine perfusion pressure (RUPP) pre-clinical rat model of PE have elevated angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA) and cerebrovascular dysfunction. Methods:Sprague Dawley rats had RUPP surgery with/without AT1-AA inhibitor ('n7AAc'144 µg/day) osmotic minipumps. Mean arterial pressure (MAP), CBF autoregulation, blood brain barrier (BBB) permeability, cerebral edema, oxidative stress, and eNOS were assessed. Results:'n7AAc' improved MAP, restored CBF autoregulation, prevented cerebral edema, elevated oxidative stress, and increased phosphorylated eNOS protein in RUPP rats. Conclusion:Inhibiting the AT1-AA in placental ischemic rats prevents hypertension, cerebrovascular dysfunction, and improves cerebral metabolic function.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/imunologia , Animais , Autoanticorpos , Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/fisiologia , Feminino , Homeostase/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos
4.
Int J Mol Sci ; 21(8)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331392

RESUMO

Degenerin proteins, such as the beta epithelial Na+ channel (ßENaC), are essential in the intracellular signaling of pressure-induced constriction, an important vascular smooth muscle cell (VSMC) function. While certain cytokines reduce ENaC protein in epithelial tissue, it is unknown if interleukin-17 (IL-17), a potent pro-inflammatory cytokine, directly mediates changes in membrane-associated ßENaC in VSMCs. Therefore, we tested the hypothesis that exposure to IL-17 reduces ßENaC in VSMCs through canonical mitogen-activated protein kinase (MAPK) signaling pathways. We treated cultured rat VSMCs (A10 cell line) with IL-17 (1-100 ng/mL) for 15 min to 16 h and measured expression of ßENaC, p38MAPK, c-jun kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). IL-17 reduced ßENaC protein expression in a concentration-dependent fashion and increased phosphorylation of p38MAPK by 15 min and JNK by 8 h. NFκB was unaffected by IL-17 in VSMCs. IL-17 treatment reduced VSMC viability but had no effect on cell death. To determine the underlying signaling pathway involved in this response, VSMCs were treated before and during IL-17 exposure with p38MAPK or JNK inhibitors. We found that JNK blockade prevented IL-17-mediated ßENaC protein suppression. These data demonstrate that the pro-inflammatory cytokine IL-17 regulates VSMC ßENaC via canonical MAPK signaling pathways, raising the possibility that ßENaC-mediated loss of VSMC function may occur in inflammatory disorders.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Interleucina-17/metabolismo , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Canais Epiteliais de Sódio/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-17/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fosforilação , Ratos
5.
Am J Physiol Heart Circ Physiol ; 318(4): H1018-H1027, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167780

RESUMO

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of ß-epithelial Na+ channel (ßENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, ßENaC is an essential signaling element in transduction of pressure-induced (aka "myogenic") constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular ßENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular ßENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of ßENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell ßENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1-100 ng/mL) for 16-24 h. TNF-α reduced ßENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated ßENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced ßENaC-mediated vascular function.NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular ß-epithelial sodium channel (ßENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced ßENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.


Assuntos
Circulação Cerebrovascular , Canais Epiteliais de Sódio/metabolismo , Músculo Liso Vascular/metabolismo , Pré-Eclâmpsia/etiologia , Fator de Necrose Tumoral alfa/sangue , Animais , Pressão Sanguínea , Linhagem Celular , Células Cultivadas , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Canais Epiteliais de Sódio/genética , Feminino , Homeostase , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/efeitos dos fármacos , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/farmacologia
6.
Alcohol Clin Exp Res ; 40(11): 2320-2328, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27647657

RESUMO

BACKGROUND: Ethanol (EtOH) neurotoxicity can result in devastating effects on brain and behavior by disrupting homeostatic signaling cascades and inducing cell death. One such mechanism involves double-stranded RNA activated protein kinase (PKR), a primary regulator of protein translation and cell viability in the presence of a virus or other external stimuli. EtOH-mediated up-regulation of interferon-gamma (IFN-γ; the oxidative stress-inducible regulator of PKR), PKR, and its target, p53, are still being fully elucidated. METHODS: Using Western blot analysis, immunofluorescence, and linear regression analyses, changes in the IFN-γ-PKR-p53 pathway following chronic EtOH treatment in the frontal cortex of rodents were examined. The role of PKR on cell viability was also assessed in EtOH-treated cells using PKR overexpression vector and PKR inhibitor (PKRI). RESULTS: In rats chronically fed EtOH, PKR, phosphorylated PKR (p-PKR), IFN-γ, and p53 were significantly increased following chronic EtOH exposure. Linear regression revealed a significant correlation between IFN-γ and p-PKR protein levels, as well as p-PKR expression and age of EtOH exposure. Overexpression of PKR resulted in greater cell death, while use of PKRI enhanced cell viability in EtOH-treated cells. CONCLUSIONS: Chronic EtOH exposure activates the IFN-γ-PKR-p53 pathway in the frontal cortex of rodents. p-PKR expression is greater in brains of rodents exposed to EtOH at earlier ages compared to later life, suggesting a mechanism by which young brains could be more susceptible to EtOH-related brain injury. PKR and p-PKR were also colocalized in neurons and astrocytes of rats. This study provides additional insight into biochemical mechanisms underlying alcohol use disorder related neuropathology and warrants further investigation of PKR as a potential pharmacotherapeutic target to combat EtOH-related neurotoxicity, loss of protein translation and brain injury.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Interferon gama/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , eIF-2 Quinase/metabolismo , Idade de Início , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Córtex Pré-Frontal/metabolismo , Distribuição Aleatória , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
7.
Neuropharmacology ; 105: 329-340, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26805422

RESUMO

Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague-Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/enzimologia , Encefalopatias/prevenção & controle , Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/genética , Transdução de Sinais/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Transativadores/genética , Animais , Encefalopatias/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Morte Celular , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/antagonistas & inibidores , Etanol/administração & dosagem , Etanol/antagonistas & inibidores , Masculino , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
8.
Neuropsychopharmacology ; 40(6): 1373-82, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25502632

RESUMO

The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11(+/+)) vs Klf11(-/-) when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11(+/+) mice, suggesting that Klf11(+/+) mice are more severely affected by the stress model compared with Klf11(-/-) mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Transtorno Depressivo Maior/metabolismo , Lobo Frontal/metabolismo , Monoaminoxidase/metabolismo , Proteínas Repressoras/metabolismo , Estresse Psicológico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Doença Crônica , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Dominação-Subordinação , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Índice de Gravidade de Doença , Fatores de Transcrição/genética , Regulação para Cima
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