RESUMEN
Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by â¼30% in old (â¼27 months) compared with young (â¼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD.
Asunto(s)
Envejecimiento/fisiología , Antioxidantes/farmacología , Aorta Torácica/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Compuestos Organofosforados/farmacología , Ubiquinona/análogos & derivados , Animales , Antioxidantes/uso terapéutico , Aorta Torácica/fisiología , Endotelio Vascular/fisiología , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Compuestos Organofosforados/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Superóxidos/metabolismo , Ubiquinona/farmacología , Ubiquinona/uso terapéutico , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/fisiopatología , Vasodilatación/efectos de los fármacosRESUMEN
Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.
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Envejecimiento/fisiología , Endotelio Vascular/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Vasodilatación , Animales , Antioxidantes/farmacología , Óxidos N-Cíclicos/farmacología , Ciclooxigenasa 2/metabolismo , Endotelio Vascular/crecimiento & desarrollo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Inflamación/metabolismo , Masculino , Ratones , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Marcadores de Spin , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.
Asunto(s)
Lesión Renal Aguda , Compuestos Organometálicos , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Anciano , Cisplatino/farmacología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Superóxidos , Ratones Endogámicos C57BL , Riñón , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Antiinflamatorios/farmacologíaRESUMEN
RATIONALE: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. OBJECTIVE: To determine the role of ß(3)-adrenergic receptors (ß(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. METHODS AND RESULTS: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by ß(3)-AR stimulation and that in response to exercise a deficiency of ß(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. CONCLUSIONS: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of ß(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).
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Ejercicio Físico , Daño por Reperfusión Miocárdica/prevención & control , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Compuestos Nitrosos/metabolismo , Condicionamiento Físico Animal , Receptores Adrenérgicos beta 3/metabolismo , Adolescente , Adulto , Animales , Activación Enzimática , Humanos , Masculino , Ratones , Ratones Noqueados , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Óxido Nítrico/genética , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptores Adrenérgicos beta 3/genética , Factores de TiempoRESUMEN
Ageing causes arterial endothelial dysfunction that increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. The aim of the present study was to determine the role of autophagy, the cellular process of recycling damaged biomolecules, in endothelial dysfunction with ageing. In older humans, expression of autophagy markers in arterial endothelial cells was impaired by â¼50% (P <0.05) and was associated with an â¼30% (P <0.05) reduction in arterial endothelium-dependent dilatation (EDD). Similarly, in C57BL/6 control mice ageing was associated with an â¼40% decrease (P <0.05) in arterial markers of autophagy and an â¼25% reduction (P <0.05) in EDD. In both humans and mice, impaired EDD was mediated by reduced nitric oxide (NO) bioavailability and was associated with increased oxidative stress and inflammation (P <0.05). In old mice, treatment with the autophagy-enhancing agent trehalose restored expression of autophagy markers, rescued NO-mediated EDD by reducing oxidative stress, and normalized inflammatory cytokine expression. In cultured endothelial cells, inhibition of autophagy increased oxidative stress and reduced NO production, whereas trehalose enhanced NO production via an autophagy-dependent mechanism. These results provide the first evidence that autophagy is impaired with ageing in vascular tissues. Our findings also suggest that autophagy preserves arterial endothelial function by reducing oxidative stress and inflammation and increasing NO bioavailability. Autophagy-enhancing strategies may therefore have therapeutic efficacy for ameliorating age-associated arterial dysfunction and preventing CVD.
Asunto(s)
Envejecimiento/metabolismo , Arterias/metabolismo , Autofagia/fisiología , Endotelio Vascular/metabolismo , Adulto , Anciano , Animales , Arterias/crecimiento & desarrollo , Arterias/fisiopatología , Autofagia/efectos de los fármacos , Citocinas/metabolismo , Femenino , Antebrazo/irrigación sanguínea , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Estrés Oxidativo , Flujo Sanguíneo Regional , Superóxidos/metabolismo , Trehalosa/farmacología , Vasodilatación/fisiologíaRESUMEN
The ageing kidney exhibits slowly developing chronic kidney disease (CKD) and is associated with nitric oxide (NO) deficiency and increased oxidative stress. The impact of exercise on the ageing kidney is not well understood. Here, we determined whether 12 weeks of treadmill exercise can influence age-dependent CKD in old (22-24 months) Fisher 344 (F344) male rats by comparing sedentary (SED) and exercise (EX) trained rats; young (3 months) rats were also studied. In addition to renal structure and function, we assessed protein levels of various isoforms of the NO synthases (NOS) and superoxide dismutase (SOD) enzymes as well as markers of oxidative stress, in kidney cortex and medulla. Renal function as determined by plasma creatinine, proteinuria, and glomerular structural injury worsened with age and was unaffected by exercise. Ageing also increased the protein abundance of neuronal NOSß and p22phox while decreasing extracellular (EC) and copper/zinc (CuZn) SOD, in kidney cortex and medulla. H(2)O(2) content and nitrotyrosine abundance also increased in the kidney with age. None of these age-related changes were altered with exercise. However, exercise did increase renal cortical endothelial (e)NOS and EC SOD in young rats. Data indicate that exercise-induced increases in eNOS and EC SOD seen in young rats are lost with age. We conclude that chronic exercise is ineffective in reversing age-dependent CKD in the male F344 rat.
Asunto(s)
Envejecimiento/fisiología , Enfermedades Renales/fisiopatología , Riñón/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Aorta/metabolismo , Enfermedad Crónica , Peróxido de Hidrógeno/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo , Ratas , Ratas Endogámicas F344 , Superóxido Dismutasa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
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Estradiol/farmacología , Longevidad/efectos de los fármacos , Envejecimiento , Animales , Femenino , Masculino , Ratones , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Piridinio/farmacología , Caracteres SexualesRESUMEN
[Figure: see text].
Asunto(s)
Envejecimiento/fisiología , Endotelio Vascular , Mitocondrias , Nitrito de Sodio , Anciano , Animales , Biomarcadores/análisis , Biomarcadores/sangre , Suplementos Dietéticos , Monitoreo de Drogas/métodos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Humanos , Metabolómica/métodos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Animales , Estrés Oxidativo/fisiología , Nitrito de Sodio/administración & dosificación , Nitrito de Sodio/efectos adversos , Nitrito de Sodio/sangre , Resultado del TratamientoRESUMEN
OBJECTIVES: Adults born prematurely have an increased risk of early heart failure. The impact of prematurity on left and right ventricular function has been well documented, but little is known about the impact on the systemic vasculature. The goals of this study were to measure aortic stiffness and the blood pressure response to physiological stressors; in particular, normoxic and hypoxic exercise. METHODS: Preterm participants (n = 10) were recruited from the Newborn Lung Project Cohort and matched with term-born, age-matched subjects (n = 12). Aortic pulse wave velocity was derived from the brachial arterial waveform and the heart rate and blood pressure responses to incremental exercise in normoxia (21% O2 ) or hypoxia (12% O2 ) were evaluated. RESULTS: Aortic pulse wave velocity was higher in the preterm groups. Additionally, heart rate, systolic blood pressure, and pulse pressure were higher throughout the normoxic exercise bout, consistent with higher conduit artery stiffness. Hypoxic exercise caused a decline in diastolic pressure in this group, but not in term-born controls. CONCLUSIONS: In this first report of the blood pressure response to exercise in adults born prematurely, we found exercise-induced hypertension relative to a term-born control group that is associated with increased large artery stiffness. These experiments performed in hypoxia reveal abnormalities in vascular function in adult survivors of prematurity that may further deteriorate as this population ages.
Asunto(s)
Aorta/fisiopatología , Ejercicio Físico/fisiología , Hipertensión/fisiopatología , Enfermedades del Prematuro/fisiopatología , Adulto , Aorta/patología , Arterias Carótidas/patología , Femenino , Frecuencia Cardíaca , Humanos , Hipertensión/etiología , Hipertensión/patología , Enfermedades del Prematuro/patología , Masculino , Análisis de la Onda del Pulso/métodos , Sobrevivientes , Rigidez Vascular , Adulto JovenRESUMEN
Reduced availability of tetrahydrobiopterin (BH(4)) contributes to the age-related decline of nitric oxide (NO)-mediated vasodilatation of soleus muscle arterioles. Depending on availability of substrate and/or necessary co-factors, endothelial nitric oxide synthase (eNOS) can generate NO and/or superoxide (O(2)(-)). We evaluated the effects of age and chronic exercise on flow-induced vasodilatation and levels of NO and O(2)(-) in soleus muscle arterioles. Young (3 months) and old (22 months) male rats were exercise trained or remained sedentary (SED) for 10 weeks. Flow-stimulated NO and O(2)(-), as well as BH(4) and l-arginine content, were determined in soleus muscle arterioles. Flow-induced vasodilatation was assessed under control conditions and during the blockade of O(2)(-) and/or hydrogen peroxide. Exercise training enhanced flow-induced vasodilatation in arterioles from young and old rats. Old age reduced, and exercise training restored, BH(4) content and flow-stimulated NO availability. Flow-stimulated, eNOS-derived O(2)(-) levels were higher in arterioles from old SED compared to those from young SED rats. Exercise training increased flow-stimulated eNOS-derived O(2)(-) levels in arterioles from young but not old rats. O(2)(-) scavenging with Tempol reduced flow-induced vasodilatation from all groups except young SED rats. Addition of catalase to Tempol-treated arterioles eliminated flow-induced vasodilatation in arterioles from all groups. Catalase reduced flow-induced vasodilatation from all groups. In Tempol-treated arterioles, flow-induced vasodilatation was restored by deferoxamine, an iron chelator. These data indicate that uncoupling of eNOS contributes to the age-related decline in flow-induced vasodilatation; however, reactive oxygen species are required for flow-induced vasodilatation in soleus muscle arterioles from young and old rats.
Asunto(s)
Envejecimiento/metabolismo , Arteriolas/metabolismo , Músculo Esquelético/irrigación sanguínea , Óxido Nítrico Sintasa de Tipo III/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Antioxidantes/farmacología , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Óxidos N-Cíclicos/farmacología , Peróxido de Hidrógeno/metabolismo , Masculino , Modelos Animales , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Oxígeno/metabolismo , Ratas , Ratas Endogámicas F344 , Especies Reactivas de Oxígeno/metabolismo , Marcadores de Spin , Resistencia Vascular/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
Aging diminishes myogenic tone in arterioles from skeletal muscle. Recent evidence indicates that both large-conductance Ca2+-activated (BKCa) and voltage-dependent (KV) K+ channels mediate negative feedback control of the myogenic response. Thus we tested the hypothesis that aging increases the contributions of KV and BKCa channels to myogenic regulation of vascular tone. Because myogenic responsiveness differs between oxidative and glycolytic muscles, we predicted that KV and BKCa channel contributions to myogenic responsiveness vary with fiber type. Myogenic responses of first-order arterioles from the gastrocnemius and soleus muscles of 4- and 24-mo-old Fischer 344 rats were evaluated in the presence and absence of 4-aminopyridine (5 mM) or iberiotoxin (30 nM), inhibitors of KV and BKCa, respectively. 4-Aminopyridine enhanced myogenic tone with aging and normalized age-related differences in both muscle types. By contrast, iberiotoxin eliminated age-related differences in soleus arterioles and had no effect in gastrocnemius vessels. KV1.5 is an integral component of KV channels in vascular smooth muscle; therefore, we determined the relative protein expression of KV1.5, as well as BKCa, in soleus and gastrocnemius arterioles. Immunoblot analysis revealed no differences in KV1.5 protein with aging or between variant fiber types, whereas BKCa protein levels declined with age in arterioles from both muscle groups. Collectively, these results suggest that the contribution of BKCa to myogenic regulation of vascular tone changes with age in soleus muscle arterioles, whereas increased KV channel expression and negative feedback regulation of myogenic tone increases with advancing age in arterioles from both oxidative and glycolytic muscles.
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Envejecimiento/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Liso Vascular/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Potasio/metabolismo , Vasoconstricción , Factores de Edad , Animales , Arteriolas/metabolismo , Relación Dosis-Respuesta a Droga , Retroalimentación Fisiológica , Glucólisis , Técnicas In Vitro , Canal de Potasio Kv1.5/antagonistas & inhibidores , Canal de Potasio Kv1.5/metabolismo , Canales de Potasio de Gran Conductancia Activados por el Calcio/antagonistas & inhibidores , Masculino , Músculo Esquelético/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Oxidación-Reducción , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Ratas , Ratas Endogámicas F344 , Vasoconstricción/efectos de los fármacosRESUMEN
Blunted nocturnal dipping in blood pressure (BP) is associated with increased cardiovascular disease (CVD) risk in middle-aged/older adults. The prevalence of blunted nocturnal BP dipping is higher in persons with obesity and diabetes, conditions that are also associated with elevated aortic stiffness and inflammation. Therefore, we hypothesized that elevated glycemia, inflammation and aortic stiffness would be inversely associated with the magnitude of nocturnal systolic BP dipping among middle-aged/older adults with obesity at high CVD risk. Twenty-four hour ambulatory BP monitoring, aortic stiffness (carotid-femoral pulse wave velocity, CF-PWV), hemoglobin A1c (HbA1c) and inflammation (C-reactive protein, CRP) were measured in 86 middle-aged/older adults with obesity and at least one other CVD risk factor (age 40-74 years; 34 male/52 female; body mass index=36.7±0.5 kg m-2; HbA1c=5.7±0.04%). In the entire cohort, CRP (ß=0.40±0.20, P=0.04), but not HbA1c or CF-PWV was independently associated with systolic BP dipping percent (Model R2=0.07, P=0.12). In stratified (that is, presence or absence of prediabetes) multiple linear regression analysis, HbA1c (ß=6.24±2.6, P=0.02) and CRP (ß=0.57±0.2, P=0.01), but not CF-PWV (ß=0.14± 2.6, P=0.74), were independently associated with systolic BP dipping percent (Model R2=0.32, P<0.01) in obese adults with prediabetes but were absent in obese adults without prediabetes (Model R2=0.01 P=0.95). However, nocturnal systolic BP dipping percent (P=0.65), CF-PWV (P=0.68) and CRP (P=0.59) were similar between participants with and without prediabetes. These data suggest that impaired long-term glycemic control and higher inflammation may contribute partly to blunted BP dipping in middle-aged/older adults with obesity-related prediabetes.
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Presión Sanguínea/fisiología , Proteína C-Reactiva/metabolismo , Ritmo Circadiano/fisiología , Hemoglobina Glucada/metabolismo , Obesidad/fisiopatología , Estado Prediabético/fisiopatología , Adulto , Anciano , Glucemia/metabolismo , Monitoreo Ambulatorio de la Presión Arterial , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones , Estado Prediabético/sangre , Estado Prediabético/etiología , Rigidez Vascular/fisiologíaRESUMEN
Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.
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Adiponectina/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/citología , Citocinas/genética , Citocinas/metabolismo , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Adiponectina/líquido cefalorraquídeo , Adiponectina/farmacología , Tejido Adiposo/metabolismo , Adulto , Anciano , Animales , Encéfalo/metabolismo , Células Endoteliales/efectos de los fármacos , Femenino , Semivida , Humanos , Masculino , Ratones , Persona de Mediana Edad , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Adiponectina , Receptores de Superficie Celular/metabolismo , Suero/metabolismoRESUMEN
Mitochondrial dysregulation and associated excessive reactive oxygen species (mtROS) production is a key source of oxidative stress in aging arteries that reduces baseline function and may influence resilience (ability to withstand stress). We hypothesized that voluntary aerobic exercise would increase arterial resilience in old mice. An acute mitochondrial stressor (rotenone) caused greater (further) impairment in peak carotid EDD in old (~27 mo., OC, n=12; -32.5±-10.5%) versus young (~7 mo., YC n=11; -5.4±- 3.7%) control male mice, whereas arteries from young and old exercising (YVR n=10 and OVR n=11, 10-wk voluntary running; -0.8±-2.1% and -8.0±4.9%, respectively) mice were protected. Ex-vivo simulated Western diet (WD, high glucose and palmitate) caused greater impairment in EDD in OC (-28.5±8.6%) versus YC (-16.9±5.2%) and YVR (-15.3±2.3%), whereas OVR (-8.9±3.9%) were more resilient (not different versus YC). Simultaneous ex-vivo treatment with mitochondria-specific antioxidant MitoQ attenuated WD-induced impairments in YC and OC, but not YVR or OVR, suggesting that exercise improved resilience to mtROS-mediated stress. Exercise normalized age-related alterations in aortic mitochondrial protein markers PGC-1α, SIRT-3 and Fis1 and augmented cellular antioxidant and stress response proteins. Our results indicate that arterial aging is accompanied by reduced resilience and mitochondrial health, which are restored by voluntary aerobic exercise.
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Envejecimiento/fisiología , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Condicionamiento Físico Animal/fisiología , Rigidez Vascular , Factores de Edad , Animales , Antioxidantes/farmacología , Arterias Carótidas/fisiopatología , Endotelio Vascular/metabolismo , Humanos , Masculino , Ratones , Proteínas Mitocondriales/metabolismo , Especies Reactivas de Oxígeno , Enfermedades Vasculares/fisiopatología , Enfermedades Vasculares/prevención & controlRESUMEN
We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress.
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Envejecimiento/patología , Suplementos Dietéticos , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Mononucleótido de Nicotinamida/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Elasticidad , Endotelio Vascular/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Óxido Nítrico/farmacología , Sirtuina 1/metabolismo , Superóxido Dismutasa/metabolismo , Rigidez Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically (P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased ß-stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial.
Asunto(s)
Envejecimiento/efectos de los fármacos , Aorta/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Nitrito de Sodio/farmacología , Anciano , Envejecimiento/metabolismo , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Índice de Masa Corporal , Arteria Braquial/efectos de los fármacos , Arteria Braquial/metabolismo , Arterias Carótidas/metabolismo , Suplementos Dietéticos , Método Doble Ciego , Elasticidad/efectos de los fármacos , Femenino , Humanos , Masculino , Metahemoglobina/metabolismo , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Análisis de la Onda del Pulso/métodos , Rigidez Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
AIM: We tested the hypothesis that short-term oral sodium nitrite supplementation would improve vascular dysfunction in obese, diabetic mice. METHODS AND RESULTS: Vascular function was determined in control mice and in db/db mice receiving drinking water with or without sodium nitrite (50 mg/L) for 5 weeks. Nitrite supplementation increased plasma nitrite concentrations in db/db mice (0.19±0.02 µM vs 0.80±0.26 µM; p < 0.05). Db/db mice had lower endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine versus heterozygous control mice (71.2% ± 14.3% vs 93% ± 7.0%; p < 0.05), and sodium nitrite supplementation restored endothelium-dependent dilation to control levels (92.9% ± 2.3% vs 93% ± 7.0%; p < 0.05). The improvement in endothelial function was accompanied by a reduction in intrinsic stiffness, but not by alterations in plasma or vascular markers of inflammation. CONCLUSION: These data suggest that sodium nitrite may be a novel therapy for treating diabetes-related vascular dysfunction; however, the mechanisms of improvement are unknown.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/tratamiento farmacológico , Nitrito de Sodio/administración & dosificación , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificación , Administración Oral , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Heterocigoto , Homocigoto , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación Puntual , Receptores de Leptina/genética , Nitrito de Sodio/sangre , Rigidez Vascular/efectos de los fármacos , Vasodilatadores/sangreRESUMEN
Aging is associated with motor declines that lead to functional limitations and disability, necessitating the development of therapies to slow or reverse these events. We tested the hypothesis that sodium nitrite supplementation attenuates declines in motor function in older C57BL/6 mice. Motor function was assessed using a battery of tests (grip strength, open-field distance, rota-rod endurance) in old animals (age 20-24 mo) at baseline and after 8 wk of sodium nitrite (old nitrite, n = 22, 50 mg/liter) or no treatment (old control, n = 40), and in young reference animals (3 mo, n = 87). Eight weeks of sodium nitrite supplementation improved grip strength (old nitrite, +12.0 ± 14.9% vs. old control, +1.5 ± 15.2%, P < 0.05) and open field distance (old nitrite, +9.5 ± 7.7%, P < 0.01 vs. old control, -28.1 ± 2.0%) and completely restored rota-rod endurance-run time (old nitrite, +3.2 ± 7.1%, P < 0.01 vs. old control, -21.5 ± 7.2%; old nitrite after treatment P > 0.05 vs. young reference). Inflammatory cytokines were markedly increased in quadriceps of old compared with young reference animals (by ELISA, interleukin-1ß [IL-1ß] 3.86 ± 2.34 vs. 1.11 ± 0.74, P < 0.05; interferon-gamma [INF-γ] 8.31 ± 1.59 vs. 3.99 ± 2.59, P < 0.01; tumor necrosis factor-alpha [TNF-α] 1.69 ± 0.44 vs. 0.76 ± 0.30 pg/ml, P < 0.01), but were reduced to young reference levels after treatment (old nitrite, IL-1ß 0.67 ± 0.95; INF-γ 5.22 ± 2.01, TNF-α 1.21 ± 0.39 pg/ml, P < 0.05 vs. old control, P > 0.05 vs. young reference). Cytokine expression and treatment (old nitrite vs. old control) predicted strength (R(2) = 0.822, P < 0.001, IL-1ß, INF-γ, group), open field distance (R(2) = 0.574, P < 0.01, IL-1ß, group) and endurance run time (R(2) = 0.477, P < 0.05, INF-γ). Our results suggest that sodium nitrite improves motor function in old mice, in part by reducing low-grade inflammation in muscle.
Asunto(s)
Envejecimiento/efectos de los fármacos , Inflamación/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Nitrito de Sodio/farmacología , Animales , Citocinas/metabolismo , Suplementos Dietéticos , Evaluación Preclínica de Medicamentos , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Nitratos/sangre , Nitritos/sangre , Nitrito de Sodio/uso terapéuticoRESUMEN
Aging is the major risk factor for cardiovascular diseases (CVD). This is attributable primarily to adverse changes in arteries, notably, increases in large elastic artery stiffness and endothelial dysfunction mediated by inadequate concentrations of the vascular-protective molecule, nitric oxide (NO), and higher levels of oxidative stress and inflammation. Inorganic nitrite is a promising precursor molecule for augmenting circulating and tissue NO bioavailability because it requires only a one-step reduction to NO. Nitrite also acts as an independent signaling molecule, exerting many of the effects previously attributed to NO. Results of recent studies indicate that nitrite may be effective in the treatment of vascular aging. In old mice, short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness, and ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation. These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation, and may be linked to increases in mitochondrial biogenesis and health. Increasing nitrite levels via dietary intake of nitrate appears to have similarly beneficial effects in many of the same physiological and clinical settings. Several clinical trials are being performed to determine the broad therapeutic potential of increasing nitrite bioavailability on human health and disease, including studies related to vascular aging. In summary, inorganic nitrite, as well as dietary nitrate supplementation, represents a promising therapy for treatment of arterial aging and prevention of age-associated CVD in humans.
Asunto(s)
Envejecimiento/efectos de los fármacos , Arterias/efectos de los fármacos , Arterias/crecimiento & desarrollo , Suplementos Dietéticos , Nitritos/uso terapéutico , Animales , Cardiotónicos/farmacología , Enfermedades Cardiovasculares/fisiopatología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Humanos , Infusiones Intravenosas , Ratones , Nitratos/fisiología , Óxido Nítrico/fisiología , Factores de Riesgo , Nitrito de Sodio/administración & dosificación , Nitrito de Sodio/farmacología , Rigidez Vascular/fisiologíaRESUMEN
We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4-6 months), old (26-28 months), and old treated with 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide scavenger (1 mm in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater large artery stiffness assessed by aortic pulse wave velocity (aPWV, 436 ± 9 vs. 344 ± 5 cm s(-1)) and intrinsic mechanical testing (3821 ± 427 vs. 1925 ± 271 kPa) (both P < 0.05). TEMPOL treatment in old reversed both measures of arterial stiffness. Aortic PVAT superoxide production was greater in old (P < 0.05 vs. Y), which was normalized with TEMPOL. Compared with young, old controls had greater pro-inflammatory proteins in PVAT-conditioned media (P < 0.05). Young recipient mice transplanted with PVAT from old compared with young donors for 8 weeks had greater aPWV (409 ± 7 vs. 342 ± 8 cm s(-1)) and intrinsic mechanical properties (3197 ± 647 vs. 1889 ± 520 kPa) (both P < 0.05), which was abolished with TEMPOL supplementation in old donors. Tissue-cultured aortic segments from old in the presence of PVAT had greater mechanical stiffening compared with old cultured in the absence of PVAT and old with PVAT and TEMPOL (both, P < 0.05). In addition, PVAT-derived superoxide was associated with arterial wall hypertrophy and greater adventitial collagen I expression with aging that was attenuated by TEMPOL. Aging or TEMPOL treatment did not affect blood pressure. Our findings provide evidence for greater age-related superoxide production and pro-inflammatory proteins in PVAT, and directly link superoxide signaling in PVAT to large elastic artery stiffness.