RESUMEN
Soluble guanylate cyclase (sGC) plays an important role in maintaining vascular homeostasis, as an acceptor for the biological messenger nitric oxide (NO). However, only reduced sGC (with a ferrous heme) can be activated by NO; oxidized (ferric heme) and apo (absent heme) sGC cannot. In addition, the proportions of reduced, oxidized, and apo sGC change under pathological conditions. Although diseased blood vessels often show decreased NO bioavailability in the vascular wall, a shift of sGC heme redox balance in favor of the oxidized/apo forms can also occur. Therefore, sGC is of growing interest as a drug target for various cardiovascular diseases. Notably, the balance between NO-sensitive reduced sGC and NO-insensitive oxidized/apo sGC in the body is regulated in a reversible manner by various biological molecules and proteins. Many studies have attempted to identify endogenous factors and determinants that influence this redox state. For example, various reactive nitrogen and oxygen species are capable of inducing the oxidation of sGC heme. Conversely, a heme reductase and some antioxidants reduce the ferric heme in sGC to the ferrous state. This review summarizes the factors and mechanisms identified by these studies that operate to regulate the sGC heme redox state.
Asunto(s)
Hemo , Óxido Nítrico , Guanilato Ciclasa/metabolismo , Hemo/metabolismo , Óxido Nítrico/metabolismo , Nitrógeno , Oxidación-Reducción , Oxidorreductasas/metabolismo , Oxígeno , Guanilil Ciclasa Soluble/metabolismoRESUMEN
Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas. Renovascular hypertension was induced by partially clipping the left renal artery (2-kidneys, 1-clip; 2K1C) for 10 weeks. Systolic, diastolic, and mean arterial pressures were significantly increased in the 2K1C group when compared with the sham group. In addition, plasma thiobarbituric acid reactive substances and aortic superoxide generation were significantly enhanced in the 2K1C group when compared with those in the sham group. The vasorelaxant response of isolated aortas to the sGC stimulator BAY 41-2272 (NO-sensitive sGC agonist) was comparable between the sham and 2K1C groups. Likewise, the sGC activator BAY 60-2770 (NO-insensitive sGC agonist)-induced relaxation did not differ between the sham and 2K1C groups. In addition, the cGMP mimetic 8-Br-cGMP (protein kinase G agonist) induced similar relaxation in both groups. Furthermore, there were no differences in BAY 41-2272-stimulated and BAY 60-2770-stimulated cGMP generation between the groups. These findings suggest that the balance between NO-sensitive and NO-insensitive forms of sGC is maintained during renovascular hypertension. Therefore, sGC might not be responsible for the reduced NO bioavailability observed during renovascular hypertension.
Asunto(s)
Guanilato Ciclasa , Hipertensión Renovascular , Animales , Aorta , GMP Cíclico , Óxido Nítrico , Ratas , Guanilil Ciclasa SolubleRESUMEN
This study aimed to investigate how atherosclerosis affects the soluble guanylate cyclase (sGC) system in coronary arteries. Rabbits were fed a normal diet for 12 weeks (N group) or a diet containing high cholesterol (1%) for 4 weeks (S-HC group) and 12 weeks (L-HC group). Cholesterol deposition in the intima of coronary arteries was observed in the S-HC group, but the formation of an atherosclerotic plaque was not observed. In contrast, a major plaque developed in the L-HC group. The relaxant response of isolated coronary arteries to sodium nitroprusside (SNP, nitric oxide donor) was not different between the N and S-HC groups, whereas the response in the L-HC group was markedly attenuated. The relaxation induced by BAY 60-2770 (sGC activator) tended to be augmented in the S-HC group, but it was significantly impaired in the L-HC group compared to that in the N group. sGC ß1 immunostaining was equally detected in the medial layer of the arteries among the N, S-HC, and L-HC groups. In addition, a strong staining was observed in the plaque region of the L-HC group. cGMP levels in the arteries stimulated with SNP were identical in the N and S-HC groups and slightly lower in the L-HC group than the other groups. BAY 60-2770-stimulated cGMP formation tended to be increased in the S-HC and L-HC groups. These findings suggest that the sGC system was not normal in atherosclerotic coronary arteries. The redox state of sGC and the distribution pattern are likely to change with the progression of atherosclerosis.
Asunto(s)
Colesterol en la Dieta/administración & dosificación , Vasos Coronarios/efectos de los fármacos , Guanilil Ciclasa Soluble/metabolismo , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Colesterol en la Dieta/sangre , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Vasos Coronarios/fisiología , GMP Cíclico/metabolismo , Masculino , ConejosRESUMEN
Cigarette smoking induces vascular endothelial dysfunction characterized by impaired nitric oxide (NO) bioavailability. There are two types of soluble guanylate cyclase (sGC), which is a cellular target of NO: NO-sensitive reduced form (the heme moiety with a ferrous iron) and NO-insensitive oxidized (the heme moiety with a ferric iron)/heme-free form. This study investigated the influence of cigarette smoking on NO-sensitive and NO-insensitive sGC-mediated vascular tone regulation in organ chamber experiments with isolated rat and human arteries. The rats were subcutaneously administered phosphate-buffered saline (PBS), nicotine-free cigarette smoke extract (N(-)-CSE) or nicotine-containing cigarette smoke extract (N(+)-CSE) for 4 weeks. Plasma thiobarbituric acid reactive substance (TBARS) levels were higher in the N(+)-CSE group than those in the N(-)-CSE group, and TBARS levels for these groups were higher than those for the PBS group. In the aorta and the pulmonary artery in rats administered N(-)-CSE or N(+)-CSE, acetylcholine-induced relaxation was significantly impaired compared with that in rats administered PBS; there was no significant difference in the relaxation between the N(-)-CSE and N(+)-CSE groups. However, sodium nitroprusside (NO-sensitive sGC stimulant)- and BAY 60-2770 (NO-insensitive sGC stimulant)-induced relaxations were not different among the three groups, regardless of the vessel type. In addition, in the human gastroepiploic artery, the relaxant responses to these sGC-targeting drugs were identical between nonsmokers and smokers. These findings suggest that NO-sensitive and NO-insensitive sGC-mediated vascular tone regulation functions normally even in blood vessels damaged by cigarette smoking.
Asunto(s)
Fumar Cigarrillos/fisiopatología , Arteria Gastroepiploica/fisiopatología , Óxido Nítrico/fisiología , Arteria Pulmonar/fisiopatología , Guanilil Ciclasa Soluble/fisiología , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Adulto , Animales , Aorta/efectos de los fármacos , Femenino , Arteria Gastroepiploica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Donantes de Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Arteria Pulmonar/efectos de los fármacos , Ratas , Especies Reactivas de Oxígeno/sangre , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vasodilatación/fisiología , Adulto JovenRESUMEN
BACKGROUND/AIMS: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators. METHODS: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry. RESULTS: At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury. CONCLUSION: Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC.
Asunto(s)
Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , GMP Cíclico/metabolismo , Activadores de Enzimas/farmacología , Hidrocarburos Fluorados/farmacología , Músculo Liso Vascular/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Nitrito de Sodio/farmacología , Guanilil Ciclasa Soluble/metabolismo , Vasodilatación/efectos de los fármacos , Angioplastia de Balón , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/enzimología , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/enzimología , Traumatismos de las Arterias Carótidas/patología , Modelos Animales de Enfermedad , Activación Enzimática , Masculino , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Ratas Sprague-Dawley , Sistemas de Mensajero Secundario , Factores de TiempoRESUMEN
BACKGROUND: The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.MethodsâandâResults:The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end). Concentration-response curves for vasoconstrictors (phenylephrine, prostaglandin F2α, and endothelin-1) and vasodilators (carperitide, nitroglycerin, and nifedipine) were then established using organ baths. All the vasoconstrictors and vasodilators produced concentration-dependent responses in each section. As the concentration of the vasoconstrictors increased, segments at the distal section showed a significantly greater contraction than those at the middle and proximal sections regardless of the type of vasoconstrictor. The effective concentration of drugs that caused 50% of the maximal response for endothelin-1 was significantly greater in the distal section than that in the proximal sections. No significant difference was found in vasodilators-induced relaxation. CONCLUSIONS: The contractility increases toward to the end of the GEA. Clinically, the distal portion of the GEA should be trimmed off and not be used as an anastomotic site wherever possible.
Asunto(s)
Arteria Gastroepiploica/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Dinoprost/farmacología , Relación Dosis-Respuesta a Droga , Endotelina-1/farmacología , Humanos , Fenilefrina/farmacología , Vasoconstricción/fisiologíaRESUMEN
Nitroglycerin is commonly used as an antispasmodic for treating spasm of coronary artery bypass grafts. This study investigated whether the presence of renal failure affects reactivity to nitroglycerin in internal thoracic arteries obtained from patients undergoing coronary bypass surgery. The patients were divided into three groups according to estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): without renal failure (60 ≤ eGFR, n = 13), with moderate renal failure (30 ≤ eGFR < 60, n = 10), and with severe renal failure (eGFR < 30, n = 10). Organ chamber technique was used to evaluate concentration-related responses of isolated internal thoracic arteries to vasodilators. Nitroglycerin induced a concentration-dependent relaxation, which was significantly augmented in patients with severe but not moderate renal failure than in those without renal failure. In addition, there was a negative correlation between eGFR and the relaxant efficacy of nitroglycerin (P = 0.016). On the other hand, relaxant responses to BAY 60-2770 (which enhances cGMP generation as with nitroglycerin) were similar among three grades of renal function. An inverse relationship of eGFR to the relaxant efficacy of BAY 60-2770 was not observed, either (P = 0.314). These findings suggest that severe renal failure specifically potentiates nitroglycerin-induced relaxation in internal thoracic artery grafts.
Asunto(s)
Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria/cirugía , Arterias Mamarias/fisiopatología , Nitroglicerina/farmacología , Insuficiencia Renal/complicaciones , Vasodilatación/efectos de los fármacos , Anciano , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Periodo Intraoperatorio , Masculino , Arterias Mamarias/efectos de los fármacos , Insuficiencia Renal/fisiopatología , Vasodilatadores/farmacologíaRESUMEN
N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Células Endoteliales/efectos de los fármacos , Epóxido Hidrolasas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Acetilcolina/farmacología , Alimentación Animal/análisis , Animales , Antígenos CD , Aorta/efectos de los fármacos , Cadherinas , Suplementos Dietéticos , Ácidos Docosahexaenoicos/química , Ácido Eicosapentaenoico/química , Células Endoteliales/metabolismo , Epóxido Hidrolasas/genética , Aceites de Pescado/química , Análisis de los Alimentos , Genes Supresores de Tumor , Proteínas Nucleares , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Arteria Renal/citología , Vasodilatación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND/AIMS: Nitroglycerin is widely used as a coronary vasodilator in the treatment of ischemic heart diseases. This study investigated the influence of hypoxia on nitroglycerin-induced relaxation in endothelium-intact and -denuded rabbit, monkey, and porcine coronary arteries. METHODS: Helically cut strips of coronary arteries were suspended in organ chambers, and isometric tension was recorded. RESULTS: Nitroglycerin concentration dependently relaxed endothelium-intact rabbit coronary arteries, which were not different under normoxic and hypoxic conditions. On the other hand, nitroglycerin-induced relaxation of endothelium-denuded arteries was significantly attenuated by hypoxia. Similarly, the relaxant response of endothelium-intact monkey coronary arteries to nitroglycerin was not affected by hypoxia, whereas that of endothelium-denuded arteries was impaired. As is the case with rabbit and monkey coronary arteries, exposure to hypoxia resulted in impaired relaxation by nitroglycerin in endothelium-denuded but not endothelium-intact porcine coronary arteries. CONCLUSION: These findings suggest that coronary endothelium plays a pivotal role in preventing the hypoxia-induced impairment of nitroglycerin responsiveness, regardless of the animal species.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Hipoxia/fisiopatología , Nitroglicerina/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Técnicas In Vitro , Macaca , Masculino , Conejos , PorcinosRESUMEN
OBJECTIVE: The balance between nitric oxide (NO)-sensitive and -insensitive forms of soluble guanylate cyclase (sGC) has been demonstrated to be disrupted in certain lifestyle-related diseases. However, it remains unclear whether type 2 diabetes results in a shift of sGC to the NO-insensitive form. This study addressed this issue in the human blood vessel. METHODS: Internal thoracic arteries were obtained from patients undergoing coronary artery bypass grafting. Helically cut strips of the arteries were suspended in organ chambers, and relaxant responses to nitroglycerin (NO-sensitive sGC stimulant) and BAY 60-2770 (NO-insensitive sGC stimulant) were assessed. RESULTS: The patients were divided into two groups according to the presence of type 2 diabetes (HbA1c: 7.0±0.3%) or its absence (HbA1c: 5.6±0.1%). Nitroglycerin-induced relaxation was not different in the arteries obtained from type 2 diabetic and non-diabetic patients. In addition, the relaxant response to BAY 60-2770 in type 2 diabetics was comparable to that observed in non-diabetics. Although the patients enrolled often had vascular risk factors other than type 2 diabetes, the relaxant responses were still in the same range in a comparison based on the number of risk factors. However, in separate experiments, the relaxant response to nitroglycerin was attenuated by pre-incubation of the arteries with ODQ (sGC imbalance inducer), whereas the relaxant response to BAY-60-2770 was augmented. CONCLUSIONS: These findings suggest that type 2 diabetes does not affect the balance between NO-sensitive and -insensitive sGC in human internal thoracic artery grafts.
Asunto(s)
GMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/enzimología , Activadores de Enzimas/farmacología , Arterias Mamarias/efectos de los fármacos , Sistemas de Mensajero Secundario/efectos de los fármacos , Guanilil Ciclasa Soluble/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Anciano , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Activación Enzimática , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Técnicas In Vitro , Masculino , Arterias Mamarias/enzimología , Arterias Mamarias/patología , Óxido Nítrico/metabolismoRESUMEN
BACKGROUND: Spasm of arterial grafts is still a clinical problem in coronary artery bypass surgery. The present study was designed to examine the effect of particulate guanylyl cyclase activator (carperitide) as an antispastic agent in internal thoracic artery and gastroepiploic artery grafts. METHODS: Isolated arterial grafts taken during surgery were studied in organ bath in three ways: the relaxing effect of carperitide on vasoconstrictor-induced precontraction; the inhibitory effect of pretreatment with carperitide on subsequent vasoconstrictor-induced contraction; and the effect of carperitide and nitroglycerin on increase of intracellular cyclic guanosine monophosphate levels. RESULTS: Carperitide produced a concentration-related, endothelium-independent relaxation contracted with potassium chloride, phenylephrine, prostaglandin F2α, or endothelin-1. Carperitide showed significantly higher potency and efficacy than nitroglycerin and nifedipine. Pretreatment with carperitide significantly attenuated the subsequent vasoconstrictor-induced contraction. Carperitide produced more cyclic guanosine monophosphate than nitroglycerin. CONCLUSIONS: Carperitide has a potent inhibitory effect on the vasoconstriction mediated by different vasoconstrictors in human internal thoracic artery and gastroepiploic artery grafts. The use of carperitide in patients during and after coronary artery bypass surgery is favored for the prevention and reversal of graft spasm.
Asunto(s)
Factor Natriurético Atrial/uso terapéutico , Puente de Arteria Coronaria/efectos adversos , Oclusión de Injerto Vascular/prevención & control , Guanilato Ciclasa/efectos de los fármacos , Arterias Mamarias/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/fisiopatología , Guanilato Ciclasa/metabolismo , Humanos , Arterias Mamarias/fisiopatología , Arterias Mamarias/trasplanteRESUMEN
OBJECTIVES: The present study was designed to evaluate the association between chronic kidney disease and the endothelial function of internal thoracic artery (ITA) grafts in patients undergoing coronary bypass surgery. An isometric tension study was performed in ITA strips obtained during surgery. Concentration-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed in ITA strips partially precontracted with phenylephrine under the inhibition of cyclooxygenase. The integrity of the endothelium was verified histologically by en-face staining of the luminal surface with the use of silver nitrate solution. RESULTS: In endothelium-intact ITA strips, ACh produced a concentration-dependent relaxation in patients with glomerular filtration rate (GFR, mL/min/1.73 m2) > 60. A concentration-dependent relaxation response also was observed in patients with GFR 30 to 60, but it was reduced significantly compared with those with GFR > 60. In both groups, removal of endothelium or treatment with nitric oxide (NO) synthase inhibitors almost abolished the ACh-induced relaxation. On the other hand, in patients with GFR < 30, mild contraction rather than relaxation was induced at a high concentration of ACh, which was modified neither by treatment with NO synthase inhibitors nor by removal of the endothelium. Vasodilator responses to sodium nitroprusside were comparable among the 3 groups. The relaxation of endothelium-intact strips to a peak ACh concentration correlated positively with GFR. This relationship held true in a multiple linear regression model, and interaction terms between GFR and other risk factors were not statistically significant. CONCLUSIONS: Endothelial function of ITA grafts to release NO is impaired at the time of surgery in patients with chronic kidney disease.
Asunto(s)
Puente de Arteria Coronaria/métodos , Enfermedad de la Arteria Coronaria/cirugía , Endotelio Vascular/fisiopatología , Arterias Mamarias/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Grado de Desobstrucción Vascular/fisiología , Vasodilatación/fisiología , Acetilcolina/farmacología , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Arterias Mamarias/efectos de los fármacos , Arterias Mamarias/trasplante , Nitroprusiato/farmacología , Insuficiencia Renal Crónica/fisiopatología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Coronary artery disease is associated with oxidative stress due to the excessive generation of free radicals in the vascular wall. This study investigated the impact of tert-butyl hydroperoxide (t-BuOOH), a peroxyl radical generator, on the redox state of soluble guanylate cyclase (sGC) in isolated monkey coronary arteries. Helically cut strips of endothelium-intact monkey coronary arteries treated with the nitric oxide synthase inhibitor NG-nitro-L-arginine (10 µmol/L) were exposed for approximately 60 min to either no drug or t-BuOOH (100 µmol/L) in the presence and absence of α-tocopherol (300 µmol/L). Relaxation and cGMP levels in response to the sGC stimulator BAY 41-2272 and the sGC activator BAY 60-2770 were assessed by organ chamber technique and enzyme immunoassay, respectively. The relaxant response to BAY 41-2272 was significantly impaired by the exposure to t-BuOOH, whereas the response to BAY 60-2770 was significantly augmented. In addition, vascular cGMP accumulation caused by BAY 41-2272 was decreased by the exposure to t-BuOOH, whereas for BAY 60-2770, it was increased. These effects of t-BuOOH were abolished by coincubation with α-tocopherol. Furthermore, correlations were observed between BAY compound-induced relaxant magnitudes and cGMP levels. Therefore, it is concluded that increased oxidative stress leads to disruption of the sGC redox state in monkey coronary arteries. This finding is of great importance for understanding coronary physiology in primates.
RESUMEN
Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits nitrergic nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid ß that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Circulación Cerebrovascular/fisiología , Músculo Liso Vascular/fisiología , Óxido Nítrico/fisiología , Fumar/fisiopatología , Enfermedad de Alzheimer/metabolismo , Endotelio Vascular/metabolismo , Humanos , Modelos Biológicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fumar/metabolismoRESUMEN
Increasing evidence support the idea that hyperhomocysteinemia (HHcy) is responsible for pathogenesis underlying cerebral, coronary, renal, and other vascular circulatory disorders and for hypertension. Impaired synthesis of nitric oxide (NO) in the endothelium or increased production of asymmetric dimethylarginine and activated oxygen species are involved in the impairment of vasodilator effects of NO. Impaired circulation in the brain derived from reduced synthesis and actions of NO would be an important triggering factor to dementia and Alzheimer's disease. Reduced actions of NO and brain hypoperfusion trigger increased production of amyloid-ß that inhibits endothelial function, thus establishing a vicious cycle for impairing brain circulation. HHcy is involved in the genesis of anginal attack and coronary myocardial infarction. HHcy is also involved in renal circulatory diseases. The homocysteine (Hcy)-induced circulatory failure is promoted by methionine and is prevented by increased folic acid and vitamin B6/B12. Eliminating poor life styles, such as smoking and being sedentary; keeping favorable dietary habits; and early treatment maintaining constitutive NOS functions healthy, reducing oxidative stresses would be beneficial in protecting HHcy-induced circulatory failures.
Asunto(s)
Circulación Cerebrovascular , Circulación Coronaria , Hiperhomocisteinemia/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Humanos , Hiperhomocisteinemia/enzimología , Hiperhomocisteinemia/fisiopatologíaRESUMEN
Aging is associated with endothelial dysfunction, defined as a reduction in nitric oxide (NO) bioavailability. Although the redox state of the NO acceptor soluble guanylate cyclase (sGC) is another determinant factor for its bioavailability and is disturbed by reactive oxygen species (ROS) known to be increased with age, it is unclear whether aging actually has an impact on vascular sGC redox equilibrium. Therefore, this study investigated this issue using two different types of compounds, the sGC stimulator BAY 41-2272 and the sGC activator BAY 60-2770. Plasma thiobarbituric acid-reactive substances (TBARS) levels were markedly higher in aged (19-20 months old) mice than in young (2-3 months old) mice, whereas superoxide levels in endothelium-denuded aortas were not different between the groups. The relaxant response of endothelium-denuded aortas to either BAY 41-2272 or BAY 60-2770 was identical in aged and young mice. In addition, the vascular cGMP production stimulated with BAY 41-2272 or BAY 60-2770 in aged mice was the same level as that in young mice. These findings suggest that aging accompanied by an increase in systemic oxidative stress does not affect vascular smooth muscle ROS generation and sGC redox equilibrium. Unless ROS are increased in vascular smooth muscle, the sGC redox equilibrium might remain unchanged.
Asunto(s)
Envejecimiento/metabolismo , Aorta Torácica/metabolismo , Guanilato Ciclasa/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Hidrocarburos Fluorados/farmacología , Masculino , Ratones , Técnicas de Cultivo de Órganos , Oxidación-Reducción/efectos de los fármacos , Pirazoles/farmacología , Piridinas/farmacología , Guanilil Ciclasa SolubleRESUMEN
Mitochondrial oxidative capacity in skeletal muscle is known to decrease in diabetic patients, and sarcopenia is a risk factor for diabetes, particularly in elderly people. We previously revealed that microRNA (miR)-494 inhibits mitochondrial biogenesis during myogenic differentiation in murine C2C12 cells and others reported that exercise regulates miR-494 levels in obese sedentary individuals with increased risk of type 2 diabetes. In this study, to investigate the therapeutic potential of miR-494, we first investigated the role of miR-494 during human skeletal myogenesis. Using human induced pluripotent stem (hiPS) cells stably transfected with the Tet/ON-myogenic differentiation 1(MYOD1) gene (MyoD-hiPS cells), we found that miR-494 expression transiently increased and was downregulated after myogenic induction. In miR-494 transfected MyoD-hiPS cells, the level of high oxidative fiber (type IIa) marker proteins specifically decreased, while no change in the total number of cells was observed. In contrast, the expression of both type I and type IIx markers was unaffected by miR-494 overexpression. Furthermore, miR-494 overexpression suppressed basal oxygen consumption rate concomitant with the inhibition of myotube formation and without significant effects on the mitochondrial content. These results suggest that miR-494 plays a novel role in the fiber type-specific skeletal myogenesis in MyoD-hiPS cells, distinct from murine C2C12 myogenesis.
Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , MicroARNs/genética , Desarrollo de Músculos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/crecimiento & desarrollo , Línea Celular , Regulación hacia Abajo , Regulación del Desarrollo de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , MicroARNs/metabolismo , Mitocondrias Musculares/metabolismo , Fibras Musculares Esqueléticas/citología , Músculo Esquelético/metabolismo , Regulación hacia ArribaRESUMEN
N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of MCP-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs). In this study, we compared the effect of DHA and EPA on the expression of Mcp-1 in rat arterial strips and rat VSMCs. DHA, but not EPA, suppressed Mcp-1 expression in arterial strips. Furthermore, DHA generated 4-hydroxy hexenal (4-HHE), an end product of n-3 polyunsaturated fatty acids (PUFAs), in arterial strips as measured by liquid chromatography-tandem mass spectrometry. In addition, 4-HHE treatment suppressed Mcp-1 expression in arterial strips, suggesting 4-HHE derived from DHA may be involved in the mechanism of this phenomenon. In contrast, Mcp-1 expression was stimulated by DHA, EPA and 4-HHE through p38 kinase and the Keap1-Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway in VSMCs. In conclusion, there is a dual effect of n-3 PUFAs on the regulation of Mcp-1 expression. Further study is necessary to elucidate the pathological role of this phenomenon.
Asunto(s)
Aldehídos/metabolismo , Quimiocina CCL2/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Células Cultivadas , Quimiocina CCL2/genética , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Técnicas In Vitro , Masculino , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Interferencia de ARN , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Espectrometría de Masas en Tándem , Factores de Tiempo , Transfección , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The production of reactive oxygen species, including hydrogen peroxide (H(2)O(2)), is increased in diseased blood vessels. Although H(2)O(2) leads to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP signaling pathway, it is not clear whether this reactive molecule affects the redox state of sGC, a key determinant of NO bioavailability. To clarify this issue, mechanical responses of endothelium-denuded rat external iliac arteries to BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), nitroglycerin (NO donor), acidified NaNO(2) (exogenous NO) and 8-Br-cGMP (cGMP analog) were studied under exposure to H(2)O(2). The relaxant response to BAY 41-2272 (pD2: 6.79 ± 0.10 and 6.62 ± 0.17), BAY 60-2770 (pD2: 9.57 ± 0.06 and 9.34 ± 0.15) or 8-Br-cGMP (pD2: 5.19 ± 0.06 and 5.24 ± 0.08) was not apparently affected by exposure to H(2)O(2). In addition, vascular cGMP production stimulated with BAY 41-2272 or BAY 60-2770 in the presence of H(2)O(2) was identical to that in its absence. On the other hand, nitroglycerin-induced relaxation was markedly attenuated by exposing the arteries to H(2)O(2) (pD2: 8.73 ± 0.05 and 8.30 ± 0.05), which was normalized in the presence of catalase (pD2: 8.59 ± 0.05). Likewise, H(2)O(2) exposure impaired the relaxant response to acidified NaNO(2) (pD2: 6.52 ± 0.17 and 6.09 ± 0.16). These findings suggest that H(2)O(2) interferes with the NO-mediated action, but the sGC redox equilibrium and the downstream target(s) of cGMP are unlikely to be affected in the vasculature.