RESUMEN
BACKGROUND AND AIMS: Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. CONCLUSION: Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. REGISTRATION: ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.
Asunto(s)
Colecalciferol/uso terapéutico , Suplementos Dietéticos , Hipertensión/tratamiento farmacológico , Mediadores de Inflamación/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Vitamina D/análogos & derivados , Vitaminas/uso terapéutico , Anciano , Austria , Biomarcadores/sangre , Colecalciferol/efectos adversos , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/inmunología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/diagnóstico , Vitaminas/efectos adversosRESUMEN
BACKGROUND Studies in ApoE knockout mice have shown that pseudolaric acid B (PB) can act as an immunomodulatory drug and attenuate atherosclerosis progression by modulating monocyte/macrophage phenotypes. Our previous study demonstrated that high salt intake could shift the phenotype of monocytes/macrophages to an inflammatory phenotype, and that this shift was related to hypertension and hypertensive left ventricular (LV) remodeling. However, no comprehensive assessment of the effects of PB on hypertensive LV remodeling has been conducted. MATERIAL AND METHODS In this study, RAW264.7 macrophages cultured with different concentrations of NaCl were used to investigate the modulating effects of PB on macrophage phenotype. Furthermore, N-nitro-L-arginine methyl ester hypertensive mice were used to investigate the modulating effects of PB on monocyte phenotype. LV remodeling was investigated by echocardiography. LV morphologic staining (for cardiomyocyte hypertrophy and collagen deposition) was performed at the time of sacrifice. RESULTS The results showed that PB significantly improved the viability of RAW264.7 cells, suppressed their phagocytic and migration abilities, and inhibited their phenotypic shift to M1 macrophages. In addition, the blood pressure of PB-treated mice was significantly decreased relative to that of control mice. Furthermore, after PB treatment, the percentage of Ly6Chi monocytes was significantly decreased while that of Ly6Clo monocytes was apparently increased. Moreover, PB preserved LV function and alleviated myocardial fibrosis and cardiomyocyte hypertrophy as measured at the end of the experimental period. The transfer of monocytes from PB-treated mice to hypertensive mice achieved the same effects. CONCLUSIONS Together, these findings indicate that PB exerts its protective effects on hypertensive LV remodeling by modulating monocyte/macrophage phenotypes and warrants further investigation.
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Diterpenos/uso terapéutico , Ventrículos Cardíacos/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Cloruro de Sodio/efectos adversos , Remodelación Ventricular/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Ecocardiografía , Hipertensión/inducido químicamente , Hipertensión/inmunología , Hipertensión/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Fenotipo , Células RAW 264.7 , Remodelación Ventricular/inmunologíaRESUMEN
BACKGROUND: Triptolide (TP), a principal bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., has been shown to have immunosuppressive/anti-inflammatory actions in vitro. Moreover, it is well established that inflammatory mechanisms contribute to the progression of hypertension-induced renal injury. Therefore, this study was performed to determine the protective effects of TP on renal injury in salt-sensitive hypertension and to identify the possible mechanisms for TP-induced protection. METHODS: Ten-week-old male C57BL/6 mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment with or without intraperitoneal administration of various concentrations of TP. RESULTS: Five weeks after the treatment, systolic blood pressure measured by tail-cuff plethysmography increased in DOCA-salt-treated mice, but no difference was found between DOCA-salt-treated mice with or without TP treatment. Treatment with TP dose-dependently attenuated increments in urinary albumin and 8-isoprostane excretion, and glomerulosclerosis and tubulointerstitial injury and fibrosis in DOCA-salt-treated mice. Moreover, our data showed that treatment with TP dose-dependently inhibited DOCA-salt-induced interstitial monocyte/macrophage infiltration associated with decreases in renal levels of proinflammatory cytokine/chemokine and adhesion molecule, as well as renal activated NF-κB concentrations. Our results also demonstrated that suppression of inflammatory responses with dexamethasone, an immunosuppressive agent, alleviated DOCA-salt hypertension-induced renal injury. CONCLUSIONS: TP treatment induced renal protection associated with inhibition of monocyte/macrophage-mediated inflammatory responses without lowering blood pressure. Thus, our data for the first time indicate that TP treatment ameliorates renal injury possibly via attenuating inflammatory responses in salt-sensitive hypertension.
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Antiinflamatorios/farmacología , Diterpenos/farmacología , Hipertensión/tratamiento farmacológico , Enfermedades Renales/prevención & control , Riñón/efectos de los fármacos , Fenantrenos/farmacología , Animales , Moléculas de Adhesión Celular/metabolismo , Citocinas/metabolismo , Acetato de Desoxicorticosterona , Modelos Animales de Enfermedad , Compuestos Epoxi/farmacología , Hipertensión/etiología , Hipertensión/inmunología , Hipertensión/metabolismo , Mediadores de Inflamación/metabolismo , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/etiología , Enfermedades Renales/inmunología , Enfermedades Renales/metabolismo , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Nefrectomía , Transducción de Señal , Cloruro de Sodio DietéticoRESUMEN
Spleen qi deficiency (SQD) syndrome is one of the basic traditional Chinese medicine (TCM) syndromes related to various diseases including chronic inflammation and hypertension and guides the use of many herbal formulae. However, the biological basis of SQD syndrome has not been clearly elucidated due to the lack of appropriate methodologies. Here, we propose a network pharmacology strategy integrating computational, clinical, and experimental investigation to study the biological basis of SQD syndrome. From computational aspects, we used a powerful disease gene prediction algorithm to predict the SQD syndrome biomolecular network which is significantly enriched in biological functions including immune regulation, oxidative stress, and lipid metabolism. From clinical aspects, SQD syndrome is involved in both the local and holistic disorders, that is, the digestive diseases and the whole body's dysfunctions. We, respectively, investigate SQD syndrome-related digestive diseases including chronic gastritis and irritable bowel syndrome and the whole body's dysfunctions such as chronic fatigue syndrome and hypertension. We found innate immune and oxidative stress modules of SQD syndrome biomolecular network dysfunction in chronic gastritis patients and irritable bowel syndrome patients. Lymphocyte modules were downregulated in chronic fatigue syndrome patients and hypertension patients. From experimental aspects, network pharmacology analysis suggested that targets of Radix Astragali and other four herbs commonly used for SQD syndrome are significantly enriched in the SQD syndrome biomolecular network. Experiments further validated that Radix Astragali ingredients promoted immune modules such as macrophage proliferation and lymphocyte proliferation. These findings indicate that the biological basis of SQD syndrome is closely related to insufficient immune response including decreased macrophage activity and reduced lymphocyte proliferation. This study not only demonstrates the potential biological basis of SQD syndrome but also provides a novel strategy for exploring relevant molecular mechanisms of disease-syndrome-herb from the network pharmacology perspective.
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Medicamentos Herbarios Chinos/farmacología , Qi , Bazo/patología , Animales , Enfermedad Crónica , Síndrome de Fatiga Crónica/genética , Síndrome de Fatiga Crónica/inmunología , Gastritis/genética , Gastritis/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/genética , Hipertensión/inmunología , Síndrome del Colon Irritable/genética , Síndrome del Colon Irritable/inmunología , Linfocitos/inmunología , Ratones , Fenotipo , Mapas de Interacción de Proteínas/efectos de los fármacos , Células RAW 264.7 , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Bazo/efectos de los fármacos , Bazo/inmunología , Síndrome , Transcripción Genética/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: To gather data from studies evaluating the pro-inflammatory profile of individuals with resistant hypertension (RH), and bring a clinical update of new and potential complementary therapies to treat inflammation in RH. RECENT FINDINGS: Increases in pro-inflammatory cytokines are related to elevated blood pressure and target organ damage in RH patients. Clinical and experimental studies have shown that some biological therapies, especially TNF-α inhibitors, regulated pro- and anti-inflammatory cytokines associated with improvements in clinical outcomes, although they are not yet reported in RH. New emerging therapies to treat inflammation in RH, although promising, are still hypotheses that have not been scientifically confirmed in clinical trials. For this reason, inflammation-target treatments, such as the TNF-α and IL-6 inhibitors, should be encouraged for testing as complementary therapies in RH in order to elucidate their potential benefits.
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Antiinflamatorios/uso terapéutico , Antihipertensivos/uso terapéutico , Citocinas/inmunología , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Inflamación/inmunología , Citocinas/sangre , Humanos , Hipertensión/sangre , Inflamación/sangre , Inflamación/tratamiento farmacológicoRESUMEN
Overstimulation of the pro-inflammatory pathways within brain areas responsible for sympathetic outflow is well evidenced as a primary contributing factor to the establishment and maintenance of neurogenic hypertension. However, the precise mechanisms and stimuli responsible for promoting a pro-inflammatory state are not fully elucidated. Recent work has unveiled novel compounds derived from omega-3 polyunsaturated fatty acids (ω-3 PUFAs), termed specialized pro-resolving mediators (SPMs), which actively regulate the resolution of inflammation. Failure or dysregulation of the resolution process has been linked to a variety of chronic inflammatory and neurodegenerative diseases. Given the pathologic role of neuroinflammation in the hypertensive state, SPMs and their associated pathways may provide a link between hypertension and the long-standing association of dietary ω-3 PUFAs with cardioprotection. Herein, we review recent progress in understanding the RAS-driven pathophysiology of neurogenic hypertension, particularly in regards to the chronic low-grade neuroinflammatory response. In addition, we examine the potential for an impaired resolution of inflammation process in the context of hypertension.
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Ácidos Grasos Omega-3/inmunología , Hipertensión/inmunología , Inflamación/inmunología , Sistema Renina-Angiotensina , Animales , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Inflamación/complicaciones , Inflamación/fisiopatología , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/fisiopatologíaRESUMEN
Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.
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Antihipertensivos/uso terapéutico , Citrulina/uso terapéutico , Angiopatías Diabéticas/prevención & control , Suplementos Dietéticos , Medicina Basada en la Evidencia , Hipertensión/prevención & control , Modelos Biológicos , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Antihipertensivos/efectos adversos , Antihipertensivos/metabolismo , Antioxidantes/efectos adversos , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Citrulina/efectos adversos , Citrulina/metabolismo , Angiopatías Diabéticas/inmunología , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/fisiopatología , Suplementos Dietéticos/efectos adversos , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/inmunología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/terapia , Sarcopenia/inmunología , Sarcopenia/metabolismo , Sarcopenia/fisiopatología , Sarcopenia/prevención & control , Rigidez Vascular , Vasodilatadores/efectos adversos , Vasodilatadores/metabolismo , Vasodilatadores/uso terapéuticoRESUMEN
Studies have demonstrated that icariin plays important roles in preventing hypertension and improving myocardial hypertrophy, inflammatory and infiltration. Icariside (ICS II) is the main metabolite of icariin, which has anti-inflammatory and anti-oxidant activities and protects against ischaemic brain injury. Whether ICS II improves myocardial fibrosis in spontaneously hypertensive rats (SHRs) and the related mechanism remain unknown. Some studies have suggested that TGF-ß and the nuclear factor κB signalling pathway play a key role in the progression of myocardial fibrosis. Therefore, in the current study, we aimed to evaluate the effects of ICS II on induced myocardial fibrosis in SHRs and explore the mechanism underlying this activity. The SHRs were treated with ICS II (4, 8, and 16â¯mg/kg) via daily gavage for 12 weeks. Left ventricular function was detected using the Vevo2100 system, and the collagen area was measured by Masson staining. The results indicated that ICS II markedly improved left ventricular function and decreased the left ventricular myocardial collagen area compared with the SHR group. To further investigate the mechanism underlying this activity, we measured the protein expression of interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1), Smad2, inhibitory κB (IκB), and nuclear factor κB (NF-κB) p65 by Western blot. The results showed that ICS II inhibited NF-κB p65 expression and the TGF-ß1/Smad2 signalling pathways. In conclusion, the present results suggest that ICS II suppresses myocardial fibrosis in SHRs, and this effect might be at least partially mediated through suppression of NF-kB signalling and the TGF-ß1/Smad2 signalling pathway.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Flavonoides/uso terapéutico , Hipertensión/tratamiento farmacológico , Miocardio/patología , FN-kappa B/antagonistas & inhibidores , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Medicamentos Herbarios Chinos/administración & dosificación , Fibrosis , Flavonoides/administración & dosificación , Hipertensión/inmunología , Masculino , Ratas Endogámicas SHR , Transducción de SeñalRESUMEN
PURPOSE: Euterpe oleracea Mart. (açaí) seed extract (ASE), through its anti-hypertensive, antioxidant and anti-inflammatory properties, may be useful to treat or prevent human diseases. Several evidences suggest that oxidative stress and inflammation contribute to the pathogenesis of diabetic nephropathy; therefore, we tested the hypothesis that ASE (200 mg/kg-1day-1) prevents diabetes and hypertension-related oxidative stress and inflammation, attenuating renal injury. METHODS: Male rats with streptozotocin (STZ)-induced diabetes (D), and spontaneously hypertensive rats with STZ-induced diabetes (DH) were treated daily with tap water or ASE (D + ASE and DH + ASE, respectively) for 45 days. The control (C) and hypertensive (H) animals received water. RESULTS: The elevated serum levels of urea and creatinine in D and DH, and increased albumin excretion in HD were reduced by ASE. Total glomeruli number in D and DH, were increased by ASE that also reduced renal fibrosis in both groups by decreasing collagen IV and TGF-ß1 expression. ASE improved biomarkers of renal filtration barrier (podocin and nephrin) in D and DH groups and prevented the increased expression of caspase-3, IL-6, TNF-α and MCP-1 in both groups. ASE reduced oxidative damage markers (TBARS, carbonyl levels and 8-isoprostane) in D and DH associated with a decrease in Nox 4 and p47 subunit expression and increase in antioxidant enzyme activity in both groups (SOD, catalase and GPx). CONCLUSION: ASE substantially reduced renal injury and prevented renal dysfunction by reducing inflammation, oxidative stress and improving the renal filtration barrier, providing a nutritional resource for prevention of diabetic and hypertensive-related nephropathy.
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Antioxidantes/uso terapéutico , Nefropatías Diabéticas/prevención & control , Suplementos Dietéticos , Euterpe/química , Extractos Vegetales/uso terapéutico , Insuficiencia Renal/prevención & control , Semillas/química , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Antihipertensivos/uso terapéutico , Apoptosis , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/orina , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Experimental/inmunología , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Fibrosis , Barrera de Filtración Glomerular/inmunología , Barrera de Filtración Glomerular/metabolismo , Barrera de Filtración Glomerular/patología , Barrera de Filtración Glomerular/fisiopatología , Hipertensión/complicaciones , Hipertensión/dietoterapia , Hipertensión/inmunología , Hipertensión/fisiopatología , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Estrés Oxidativo , Ratas Endogámicas SHR , Insuficiencia Renal/complicaciones , Insuficiencia Renal/etiología , Insuficiencia Renal/metabolismoRESUMEN
The aim of the work was to study the delayed effect of lipopolysaccharide (LPS) administration on endothelial function of the aorta of rats with genetic hypertension. Further, the possibility to ameliorate LPS-induced changes by n-3 polyunsaturated fatty acids (n-3 PUFA) was tested. Rats received a bolus of 1 mg/kg LPS i.p.; n-3 PUFA were administered in the dose of 30 mg/kg daily for 10 days p.o.. Ten days after receiving of LPS, the body weight gain of rats was statistically lower compared to control rats (p < 0.05). n-3 PUFA administration to LPS rats had no effect on this parameter. The TBARS and NAGA concentrations in plasma were significantly increased in the LPS group (p < 0.05) and n-3 PUFA administration returned them to control values. In functional studies, phenylephrine (PE, 1 µmol/l) evoked contraction of aortas which was not statistically different among experimental groups. However, endothelium-dependent relaxation was depressed in the LPS group (p < 0.05) and n-3 PUFA slightly recovered it to control values. In conclusion, oxidative stress seems to be responsible for aortic endothelial dysfunction detected 10 days after administration of LPS to rats. n-3 PUFA slightly improved the function of the endothelium injured by LPS, probably thanks to their antioxidant properties. Prolonged administration of higher doses of n-3 PUFA should defend the vascular endothelium against detrimental effect of bacterial inflammation.
Asunto(s)
Aorta/efectos de los fármacos , Aorta/inmunología , Aortitis/inducido químicamente , Aortitis/inmunología , Ácidos Grasos Omega-3/administración & dosificación , Lipopolisacáridos , Animales , Aortitis/prevención & control , Interacciones Farmacológicas , Hipertensión/inmunología , Masculino , Ratas , Ratas Endogámicas SHRRESUMEN
Moringa oleifera is a plant whose fruits, roots and leaves have been advocated for traditional medicinal uses. The physicochemical analysis shows that Moringa oleifera contains more dietary polyunsaturated fatty acids (PUFA) than saturated fatty acids (SFA). The consumption of an experimental diet enriched with Moringa oleifera extracts lowered blood pressure in spontaneously hypertensive rats (SHR), but not in normotensive Wistar-Kyoto (WKY) rats as compared to rats fed an unsupplemented control diet. Anti-CD3-stimulated T cell proliferation was diminished in both strains of rats fed the Moringa oleifera. The experimental diet lowered secretion of interleukin-2 in SHR, but not in WKY rats compared with rats fed the control diet. Studies of platelets from patients with primary hypertension and from SHR support the notion that the concentration of intracellular free calcium [Ca(2+)](i) is modified in both clinical and experimental hypertension. We observed that the basal, [Ca(2+)](i) was lower in T cells of SHR than in those of WKY rats fed the control diet. Feeding the diet with Moringa oleifera extracts to WKY rats did not alter basal [Ca(2+)](i) in T cells but increased basal [Ca(2+)](i) in SHR. Our study clearly demonstrated that Moringa oleifera exerts antihypertensive effects by inhibiting the secretion of IL-2 and modulates T cell calcium signaling in hypertensive rats.
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Antihipertensivos/uso terapéutico , Señalización del Calcio/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Moringa oleifera , Extractos Vegetales/uso terapéutico , Linfocitos T/efectos de los fármacos , Animales , Antihipertensivos/aislamiento & purificación , Antihipertensivos/farmacología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Señalización del Calcio/fisiología , Hipertensión/inmunología , Hipertensión/fisiopatología , Masculino , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Hojas de la Planta , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Linfocitos T/fisiologíaRESUMEN
Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-ß (TGFß) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFß is sufficient to cause hypertension in mice. Knockout of the TGFß receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFß but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFß receptor antagonist or genetically by TGFß receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFß receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFß pathway to mediate a central inflammatory mechanism of obesity-related hypertension.
Asunto(s)
Presión Sanguínea/inmunología , ADN Mitocondrial/inmunología , Hipertensión/inmunología , Hipotálamo/inmunología , Obesidad/inmunología , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor de Crecimiento Transformador beta/inmunología , Animales , Benzamidas/farmacología , Western Blotting , ADN Mitocondrial/líquido cefalorraquídeo , ADN Mitocondrial/metabolismo , ADN Mitocondrial/farmacología , Dieta Alta en Grasa , Dioxoles/farmacología , Hipertensión/etiología , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Noqueados , Neuronas/inmunología , Neuronas/metabolismo , Obesidad/complicaciones , Proopiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/inmunología , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/inmunología , Tercer Ventrículo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.
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Hipertensión/terapia , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Derivación Arteriovenosa Quirúrgica/métodos , Derivación Arteriovenosa Quirúrgica/tendencias , Barorreflejo/fisiología , Ablación por Catéter/tendencias , Ensayos Clínicos como Asunto , Estimulación Encefálica Profunda/métodos , Estimulación Encefálica Profunda/tendencias , Venenos Elapídicos/agonistas , Medicina Basada en la Evidencia , Predicción , Humanos , Hipertensión/genética , Hipertensión/inmunología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Péptido Natriurético Tipo-C/agonistas , Neprilisina/antagonistas & inhibidores , Regeneración Nerviosa/fisiología , Norepinefrina/antagonistas & inhibidores , Péptidos/uso terapéutico , Sistema Renina-Angiotensina/fisiología , Simpatectomía/métodos , Simpatectomía/tendencias , Estimulación Eléctrica Transcutánea del Nervio/métodos , Estimulación Eléctrica Transcutánea del Nervio/tendencias , Péptido Intestinal Vasoactivo/uso terapéuticoRESUMEN
Interdisciplinary studies in the research fields of endocrinology and immunology show that obesity-associated overnutrition leads to neuroinflammatory molecular changes, in particular in the hypothalamus, chronically causing various disorders known as elements of metabolic syndrome. In this process, neural or hypothalamic inflammation impairs the neuroendocrine and autonomic regulation of the brain over blood pressure and glucose homeostasis as well as insulin secretion, and elevated sympathetic activation has been appreciated as a critical mediator. This review describes the involved physiology and mechanisms, with a focus on glucose and blood pressure balance, and suggests that neuroinflammation employs the autonomic nervous system to mediate the development of diabetes and hypertension.
Asunto(s)
Diabetes Mellitus/metabolismo , Hipertensión/metabolismo , Hipotálamo/metabolismo , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Hipernutrición/metabolismo , Sistema Nervioso Simpático/metabolismo , Animales , Sistema Nervioso Autónomo/inmunología , Sistema Nervioso Autónomo/metabolismo , Sistema Nervioso Autónomo/fisiopatología , Glucemia/metabolismo , Presión Sanguínea/fisiología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Diabetes Mellitus/inmunología , Glucosa/metabolismo , Homeostasis , Humanos , Hipertensión/inmunología , Hipertensión/fisiopatología , Hipotálamo/inmunología , Hipotálamo/fisiopatología , Inflamación , Insulina/metabolismo , Secreción de Insulina , Síndrome Metabólico/inmunología , Obesidad/inmunología , Hipernutrición/inmunología , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
Asunto(s)
Hipertensión/inmunología , Inflamación/inmunología , Inmunidad Adaptativa/fisiología , Animales , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Citocinas/deficiencia , Citocinas/fisiología , Evaluación Preclínica de Medicamentos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Hipertensión/fisiopatología , Inmunidad Innata/fisiología , Inflamación/fisiopatología , Riñón/inmunología , Riñón/patología , Riñón/fisiopatología , Activación de Linfocitos , Ratones , Ratones Noqueados , Modelos Animales , Modelos Cardiovasculares , Modelos Inmunológicos , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/fisiología , Remodelación Vascular , Rigidez VascularRESUMEN
Essential hypertension (EH) is a very common clinical disorder affecting the patient's health. Accumulating evidence indicates that immunological factors play an important role in the pathogenesis of hypertension. In the present paper, the authors introduce 1) progress of researches on the pathogenesis of hypertension from cellular immune and body fluid immune (multiple immuno-humoral factors); 2) effects of acupuncture intervention on natural killer cell activity, exercise-induced immunosuppression, circulating inflammatory factor levels and balance of cytokines; 3) blood-pressure reduction effect of acupuncture intervention by lowering circulating TNF-alpha, IL-6, matrix metalloproteinases-9, angiotensin convertase and endothelin levels, and up-regulating serum opioid peptide content, etc. to decrease inflammatory injury of the cardiovascular system. Many researches have demonstrated that acupuncture may have a positive role in improving EH in clinical practice, which may be associated with its regulative effect on immune system, but its mechanism has not been fully elucidated.
Asunto(s)
Terapia por Acupuntura , Hipertensión/inmunología , Hipertensión/terapia , Animales , Citocinas/inmunología , Hipertensión Esencial , Humanos , Sistema InmunológicoRESUMEN
OBJECTIVE: To investigate the effects of sapindus saponins on myocardial inflammation mediated by Ang II/ p38MAPK signal pathway and cardiac hypertrophy in spontaneously hypertensive rats. And also to explore the correlation of cardiac hypertrophy and inflammation. METHOD: Thirty-two 16-week-old spontaneously hypertensive rats (SHR) were randomly divided into four groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators detected were as follows: (1) left ventricular mass index (LVMI); (2) the content of Ang II and hs-CRP in plasma were determined by ELISA; (3) the protein expression of AT1R and VEGF were determined by immunohistochemical method; (4) the protein expression of p-p38MAPK in myocardial cells was determined by Western blot. RESULT: Sapindus saponins reduced LVMI, and blocked the expression level of Ang II, AT1R, p-p38MAPK, VEGF and hs-CRP in myocardial tissue. Vs the SHR model group, there were significant differences (P < 0.05 or P < 0.01). CONCLUSION: Our findings suggested that sapindus saponins could inhibited cardiac hypertrophy, the possible mechanisms may be related to the inhibition on inflammatory response mediated by Ang II/p38MAPK pathway.
Asunto(s)
Angiotensina II/inmunología , Medicamentos Herbarios Chinos/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Sapindus/química , Saponinas/administración & dosificación , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/inmunología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/inmunología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas WistarRESUMEN
Fetal glucocorticoid excess programs several adverse outcomes in adult offspring, many of which can be prevented by postnatal, dietary omega-3 (n-3) fatty acids. Here we tested 2 separate hypotheses: 1) a postnatal high-fat diet exacerbates the glucocorticoid-programmed phenotype; and 2) postnatal, dietary n-3 fatty acids rescue programmed outcomes, even in the presence of a high-fat diet challenge. Pregnant Wistar rat dams were either untreated or administered dexamethasone acetate (Dex; 0.5 µg/mL drinking water) from day 13 of pregnancy. Offspring were cross-fostered to untreated mothers and males were weaned onto a standard (Std), high-fat, low n-3 (HF), or high-fat, high n-3 (HFHn-3) diet. Prenatal Dex reduced birth weight (26%) and delayed puberty onset by 1.2 days, irrespective of postnatal diet. Prenatal Dex programmed increased blood pressure in adult offspring, an effect worsened by the postnatal HF diet. Supplementation with high n-3 fatty acids, however, prevented both the Dex and HF-induced increases in blood pressure. Prenatal Dex also programmed increased adiposity, plasma cholesterol, and plasma triglyceride levels at 6 months of age, particularly in those offspring raised on the HF diet. But again, each of these adverse outcomes was rescued by supplementation of the HF diet with n-3 fatty acids. In conclusion, the capacity of n-3 fatty acids to overcome adverse programming outcomes remains evident, even in the presence of a HF diet challenge.
Asunto(s)
Adiposidad , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Desarrollo Fetal , Glucocorticoides/metabolismo , Hiperlipidemias/prevención & control , Hipertensión/prevención & control , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/efectos adversos , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/efectos adversos , Femenino , Glucocorticoides/sangre , Hiperlipidemias/etiología , Hiperlipidemias/inmunología , Hipertensión/etiología , Hipertensión/inmunología , Masculino , Intercambio Materno-Fetal , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/inmunología , Complicaciones del Embarazo/fisiopatología , Distribución Aleatoria , Ratas , Ratas Wistar , Estrés Fisiológico , Estrés Psicológico/sangre , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatologíaRESUMEN
Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the one-year daily intake of a RES enriched (8 mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the pro-inflammatory cytokines CCL3, IL-1ß and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad de la Arteria Coronaria/dietoterapia , Citocinas/genética , Diabetes Mellitus Tipo 2/dietoterapia , Hipertensión/dietoterapia , Leucocitos Mononucleares/efectos de los fármacos , MicroARNs/genética , Estilbenos/uso terapéutico , Anciano , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/inmunología , Citocinas/inmunología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inmunología , Suplementos Dietéticos/análisis , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipertensión/complicaciones , Hipertensión/genética , Hipertensión/inmunología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Modelos Moleculares , Extractos Vegetales/uso terapéutico , Resveratrol , Transcriptoma/efectos de los fármacos , Vitis/químicaRESUMEN
BACKGROUND AND AIMS: Arterial stiffness is an independent predictor of cardiovascular disease (CVD) events and all-cause mortality and may be differentially affected by dietary fatty acid (FA) intake. The aim of this study was to investigate the relationship between FA consumption and arterial stiffness and blood pressure in a community-based population. METHODS AND RESULTS: The Caerphilly Prospective Study recruited 2398 men, aged 45-59 years, who were followed up at 5-year intervals for a mean of 17.8-years (n 787). A semi-quantitative food frequency questionnaire estimated intakes of total, saturated, mono- and poly-unsaturated fatty acids (SFA, MUFA, PUFA). Multiple regression models investigated associations between intakes of FA at baseline with aortic pulse wave velocity (aPWV), augmentation index (AIx), systolic and diastolic blood pressure (SBP, DBP) and pulse pressure after a 17.8-year follow-up--as well as cross-sectional relationships with metabolic markers. After adjustment, higher SFA consumption at baseline was associated with higher SBP (P = 0.043) and DBP (P = 0.002) and after a 17.8-year follow-up was associated with a 0.51 m/s higher aPWV (P = 0.006). After adjustment, higher PUFA consumption at baseline was associated with lower SBP (P = 0.022) and DBP (P = 0.036) and after a 17.8-year follow-up was associated with a 0.63 m/s lower aPWV (P = 0.007). CONCLUSION: This study suggests that consumption of SFA and PUFA have opposing effects on arterial stiffness and blood pressure. Importantly, this study suggests that consumption of FA is an important risk factor for arterial stiffness and CVD.