RESUMEN
Diabetes affects more than 150 million people worldwide, and it is estimated that this would increase to 299 million by the year 2025. The incidence of and mortality from cardiovascular disease are two- to eightfold higher in subjects with diabetes than in those without, coronary artery disease accounting for the large majority of deaths. Among the full spectrum of biochemical effects of high glucose, generation of oxygen-derived free radicals is one of the main pathophysiological mechanisms linking hyperglycemia to atherosclerosis, nephropathy, and cardiomyopathy. The adaptor protein p66(Shc) is implicated in mitochondrial reactive oxygen species (ROS) generation and translation of oxidative signals into apoptosis. Indeed, p66(Shc-/-) mice display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis. Accordingly, a series of studies defined the pathophysiological role of p66(Shc) in cardiovascular disease where ROS represent a substantial triggering component. As p66(Shc) modulates the production of cellular ROS, it represents a proximal node through which high glucose exerts its deleterious effects on different cell types; indeed, several studies tested the hypothesis that deletion of the p66(Shc) gene may confer protection against diabetes-related cardiovascular complications. The present review focuses on the reported evidence linking p66(Shc) signaling pathway to high glucose-associated endothelial dysfunction, atherogenesis, nephropathy, and cardiomyopathy.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Angiopatías Diabéticas/etiología , Estrés Oxidativo/fisiología , Proteínas Adaptadoras de la Señalización Shc/fisiología , Animales , Enfermedades Cardiovasculares/metabolismo , Angiopatías Diabéticas/metabolismo , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Proteínas Adaptadoras de la Señalización Shc/genética , Proteínas Adaptadoras de la Señalización Shc/metabolismo , Transducción de Señal , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de SrcRESUMEN
BACKGROUND: Sedentary aging is associated with oxidative stress and endothelial dysfunction. The aim of this study was to evaluate the relationship between long-term physical activity, plasma antioxidant status, and conduit artery endothelial function in young and older healthy men. METHODS: In young (n = 16) and older athletes (n = 16) and in matched healthy sedentary subjects, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, were measured in the brachial artery from high-resolution ultrasonography. Plasma malondialdehyde (MDA) and antioxidant capacity as total oxyradical scavenging capacity (TOSC) were also evaluated. RESULTS: We found that FMD was lower (< or =0.01) in sedentary older subjects (2.3% +/- 1.0%) as compared with older athletes (5.3% +/- 3.2%) and both sedentary (5.4% +/- 2.0%) and athletically trained (6.1% +/- 3.2%) young subjects. Sedentary older subjects showed higher (P < or = .05) MDA levels and lower (P < .0001) plasma antioxidant capacity as compared with the other subgroups, whereas in older athletes MDA levels and antioxidant capacity were similar to those observed in the young subgroups. In the whole group, FMD, but not GTN, was negatively related to age (r = -0.31, P < .05) and directly related (P < or = .01) to VO2max (r = 0.49) and TOSC against peroxyl (r = 0.69) and hydroxyl radicals (r = 0.53). In the multivariate analysis, TOSC against peroxyl radicals resulted as the most significant predictor of FMD (R2 = 0.60; P = .003). CONCLUSIONS: These results suggest that regular physical activity is associated with preserved antioxidant defenses and endothelial function in older individuals.
Asunto(s)
Envejecimiento/fisiología , Endotelio Vascular/fisiología , Ejercicio Físico/fisiología , Depuradores de Radicales Libres/sangre , Vasodilatación/fisiología , Adulto , Anciano , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiología , Humanos , Radical Hidroxilo/sangre , Estilo de Vida , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Análisis Multivariante , Nitroglicerina/farmacología , Consumo de Oxígeno , Especies Reactivas de Oxígeno/sangre , Flujo Sanguíneo Regional/fisiología , Ultrasonografía , Vasodilatadores/farmacologíaRESUMEN
Uremic patients have an increased incidence of cardiovascular disease (CVD), endothelial dysfunction and oxidative stress that can contribute to cardiovascular (CV) events. To assess the relationship between endothelial dysfunction, oxidative stress and renal failure severity, we studied 40 patients (age 57 +/- 7 yrs, 24 males) affected by chronic kidney disease (CKD) K/DOQI stage 3-5 (serum creatinine (Cr) 5.6 +/- 2.2 mg/dL) on conservative treatment, 20 uremic patients (age 57 +/- 12 yrs, 13 males) on hemodialysis (HD) and 30 healthy controls (56 +/- 12 yrs, 20 males). Before and 2 hr after oral vitamin C (2 g) administration, we measured brachial artery endothelium-dependent vasodilation (flow mediated dilation (FMD)) to reactive hyperemia following 5 min of forearm ischemia and the response to sublingual glyceril trinitrate (GTN). Measurements were made by high-resolution ultrasound and computerized analysis. FMD was lower in CKD patients than in controls (5.3 +/- 2.2 vs. 6.9 +/- 2.8%; p<0.01) and was further reduced in HD patients (3.6 +/- 2.7; p<0.01 vs. CKD patients). Response to GTN was similar in all groups. FMD was related to Cr clearance (r=0.42; p<0.01) in CKD patients, while it related inversely to Kt/V(urea) (r=-0.52; p<0.05) in HD patients. After vitamin C administration, FMD was significantly enhanced in HD (4.7 +/- 2.4%; p<0.01 vs. baseline), but not in CKD patients. Response to GTN was unaffected. However, vitamin C load reduced oxidative stress markers, and increased plasma antioxidant capability in both groups. In conclusion, the reduced endothelium-dependent dilation in the brachial artery of CKD patients is related to renal failure severity. HD patients showed a more marked alteration, which seems to be related, at least in part, to increased oxidative stress.
Asunto(s)
Endotelio Vascular/fisiopatología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Estrés Oxidativo/fisiología , Adulto , Anciano , Antihipertensivos/uso terapéutico , Ácido Ascórbico/farmacología , Arteria Braquial , Estudios de Casos y Controles , Progresión de la Enfermedad , Endotelio Vascular/efectos de los fármacos , Epoetina alfa , Eritropoyetina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Valores de Referencia , Diálisis Renal/métodos , Medición de Riesgo , Muestreo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Vasodilatación/fisiologíaRESUMEN
Nitroglycerin (glyceryl trinitrate, GTN) relaxes blood vessels primarily via activation of the soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK-I) pathway. Although the precise mechanism of sGC activation by GTN in the vascular wall is unknown, the mediatory role of nitric oxide (NO) has been postulated. We tested the GTN/NO hypothesis in different types of isolated rat and rabbit blood vessels using two novel approaches: (1) EPR spin trapping using colloid Fe(DETC)2 and (2) analysis of cGK-I-dependent phosphorylation of the vasodilator-stimulated phosphoprotein at Ser239 (P-VASP). For comparison, another organic nitrate, isosorbide dinitrate (ISDN), and endothelium-dependent vasodilator, calcium ionophore A23187, were tested. We found a marked discrepancy between GTN's strong vasoactivity (vasodilation and augmentation of P-VASP) and its poor NO donor properties. In aortas precontracted with phenylephrine, GTN, ISDN, and A23187 induced nearly full relaxations (>80%) and doubling of vascular P-VASP content at concentrations of 100 nmol/L, 100 micromol/L, and 1 micromol/L, respectively. GTN applied in vasorelaxant concentrations (10 to 1000 nmol/L) did not significantly increase the basal vascular NO production, in contrast to ISDN and A23187. The absence of GTN-derived NO was confirmed in rabbit vena cava and renal artery. A significant increase in vascular NO formation was observed only at suprapharmacological GTN concentrations (>10 micromol/L). The concentration dependency of NO formation from GTN was comparable to that of ISDN, although the latter exhibits 100-folds lower vasorelaxant potency. We conclude that GTN activates the sGC/cGMP/cGK-I pathway and induces vasorelaxation without intermediacy of the free radical NO. The full text of this article is available online at http://www.circresaha.org.
Asunto(s)
Óxido Nítrico/metabolismo , Nitroglicerina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Benomilo/farmacología , Calcimicina/farmacología , Moléculas de Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/metabolismo , Relación Dosis-Respuesta a Droga , Espectroscopía de Resonancia por Spin del Electrón , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa , Técnicas In Vitro , Ionóforos/farmacología , Dinitrato de Isosorbide/farmacología , Masculino , Proteínas de Microfilamentos , Fosfoproteínas/efectos de los fármacos , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Conejos , Ratas , Ratas Wistar , Receptores Citoplasmáticos y Nucleares/metabolismo , Arteria Renal/efectos de los fármacos , Arteria Renal/fisiología , Guanilil Ciclasa Soluble , Detección de Spin , Vasoconstrictores/farmacología , Venas Cavas/efectos de los fármacos , Venas Cavas/fisiologíaRESUMEN
To compare the effect of antihypertensive drugs on endothelium-dependent vasodilation in the peripheral conduit arteries of patients with essential hypertension, in a prospective, randomized, parallel group study, endothelial function was assessed in 168 hypertensive patients before and after 6-month treatment with randomly assigned nifedipine GITS (30 to 60 mg, n=28), amlodipine (5 to 10 mg, n=28), atenolol (50 to 100 mg, n=29), nebivolol (5 to 10 mg, n=28), telmisartan (80 to 160 mg, n=29), and perindopril (2 to 4 mg, n=28). If necessary, hydrochlorothiazide (25 mg) was added to each compound. We evaluated brachial artery flow-mediated, endothelium-dependent dilation (high-resolution ultrasound) compared with endothelium-independent response to glyceryl trinitrate (25 microg/s). Brachial artery diameter was measured by automatic computerized analysis. Forty healthy subjects were evaluated as a control group. Oxidative stress production was evaluated by measuring plasma malondialdehyde and plasma lipoperoxides; plasma antioxidant capacity was assessed as ferric-reducing antioxidant power. Hypertensive patients showed a significantly (P<0.01) lower flow-mediated dilation (5.2+/-1.9%) as compared with healthy control subjects (7.1+/-2.6%). Response to glyceryl trinitrate was similar in control subjects and patients. At baseline, blood pressure, diameter, flow-mediated dilation, and response to glyceryl trinitrate were similar in the different treatment groups. All treatments similarly reduced blood pressure, but only perindopril increased flow mediated dilation (from 5.1+/-2 to 6.4+/-2.4%; P<0.01) without modifying the response to glyceryl trinitrate. Perindopril but also telmisartan nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity. In patients with essential hypertension, ACE inhibitors appear to be the only compounds able to improve conduit artery endothelium-dependent vasodilation.
Asunto(s)
Antihipertensivos/farmacología , Arterias/citología , Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Arteria Braquial/citología , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Receptor de Angiotensina Tipo 1 , Método Simple Ciego , Vasodilatación/efectos de los fármacosRESUMEN
Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.