RESUMO
AIMS: Nitric oxide synthases (NOSs) are key enzymes regulating vascular function. Previously, we reported that ß-adrenergic (ß-AR) overstimulation, a common feature of cardiovascular diseases, did not impair endothelium-dependent vasodilation, although it resulted in endothelial NOS (eNOS) uncoupling and reduced NO bioavailability. In addition to NO, neuronal NOS (nNOS) produces H2O2, which contributes to vasodilation. However, there is limited information regarding vascular ß-AR signaling and nNOS. In the present study, we assessed the possible role of nNOS-derived H2O2 and caveolins on endothelial vasodilation function following ß-AR overstimulation. MAIN METHODS: Male C57BL/6 wild-type and nNOS knockout mice (nNOS-/-) were treated with the ß-AR agonist isoproterenol (ISO, 15 mg·kg-1·day-1, s.c.) or vehicle (VHE) for seven days. Relaxation responses of aortic rings were evaluated using wire myograph and H2O2 by Amplex Red. KEY FINDINGS: Acetylcholine- or calcium ionophore A23187-induced endothelium-dependent relaxation was similar in aortic rings from VHE and ISO. However, this relaxation was significantly reduced in aortas from ISO compared to VHE when (1) caveolae were disrupted, (2) nNOS was pharmacologically inhibited or genetically suppressed and (3) H2O2 was scavenged. NOS-derived H2O2 production was higher in the aortas of ISO mice than in those of VHE mice. Aortas from ISO-treated mice showed increased expression of caveolin-1, nNOS and catalase, while caveolin-3 expression did not change. SIGNIFICANCE: The results suggest a role of caveolin-1 and the nNOS/H2O2 vasodilatory pathway in endothelium-dependent relaxation following ß-AR overstimulation and reinforce the protective role of nNOS in cardiovascular diseases associated with high adrenergic tone.
Assuntos
Caveolina 1/fisiologia , Óxido Nítrico Sintase Tipo I/fisiologia , Receptores Adrenérgicos alfa/metabolismo , Vasodilatação/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Calcimicina/farmacologia , Ionóforos de Cálcio/farmacologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Caveolina 1/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Peróxido de Hidrogênio/metabolismo , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Vasodilatação/efeitos dos fármacos , Vasodilatação/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: SerpinB3 is a cysteine protease inhibitor involved in several biological activities. It is progressively expressed in chronic liver disease, but not in normal liver. The role in vascular reactivity of this serpin, belonging to the same family of Angiotensin II, is still unknown. Our aim was to evaluate the in vivo and in vitro effects of SerpinB3 on systemic and splanchnic hemodynamics. MATERIAL AND METHODS: Different hemodynamic parameters were evaluated by ultrasonography in two colonies of mice (transgenic for human SerpinB3 and C57BL/6J controls) at baseline and after chronic carbon tetrachloride (CCl4) treatment. In vitro SerpinB3 effect on mesenteric microvessels of 5 Wistar-Kyoto rats was analyzed measuring its direct action on: (a) preconstricted arteries, (b) dose-response curves to phenylephrine, before and after inhibition of angiotensin II type 1 receptors with irbesartan. Hearts of SerpinB3 transgenic mice and of the corresponding controls were also analyzed by morphometric assessment. RESULTS: In SerpinB3 transgenic mice, cardiac output (51.6±21.5 vs 30.1±10.8ml/min, p=0.003), hepatic artery pulsatility index (0.85±0.13 vs 0.65±0.11, p<0.001) and portal vein blood flow (5.3±3.2 vs 3.1±1.8ml/min, p=0.03) were significantly increased, compared to controls. In vitro, recombinant SerpinB3 had no direct hemodynamic effect on mesenteric arteries, but it increased their sensitivity to phenylephrine-mediated vasoconstriction (p<0.01). This effect was suppressed by inhibiting angiotensin II type-1 receptors. CONCLUSIONS: In transgenic mice, SerpinB3 is associated with a hyperdynamic circulatory syndrome-like pattern, possibly mediated by angiotensin receptors.
Assuntos
Antígenos de Neoplasias/genética , Hemodinâmica/genética , Serpinas/genética , Circulação Esplâncnica/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antígenos de Neoplasias/farmacologia , Débito Cardíaco , Hemodinâmica/efeitos dos fármacos , Artéria Hepática/diagnóstico por imagem , Artéria Hepática/fisiopatologia , Humanos , Irbesartana/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/efeitos dos fármacos , Fenilefrina/farmacologia , Fluxo Pulsátil/efeitos dos fármacos , Fluxo Pulsátil/genética , Ratos , Ratos Endogâmicos WKY , Serpinas/farmacologia , Circulação Esplâncnica/efeitos dos fármacos , Síndrome , Ultrassonografia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/genética , Vasodilatação/efeitos dos fármacos , Vasodilatação/genéticaRESUMO
Maternal obesity is associated with large-for-gestational-age (LGA) neonates and programming of obesity-related cardiovascular disease in the offspring, however, the mechanisms that lead to the later are unclear. Presently, interpretations of NO-dependent changes in vascular function in LGA newborn from obese mothers are conflicting. Adiponectin improves endothelial function by increasing eNOS activity and NO production. We propose that LGAs from obese mothers present a diminished vascular response to adiponectin; thus, affecting eNOS and AMPK activation. Chorionic arteries, umbilical cord and primary cultures of umbilical artery endothelial cells (HUAEC) were collected at term (>38 weeks) from uncomplicated singleton pregnancies of LGA and adequate-for-gestational (AGA) newborn. Vascular reactivity of chorionic plate arteries was assessed by wire myography. mRNA expression of adiponectin receptors 1 (AdipoR1) and AdipoR2 in HUAEC was determined by qPCR. Protein expression of AdipoR1, AdipoR2, AMPK, phospho-AMPKαThr172 , eNOS, and phospho-eNOSSer1177 after stimulation with AdipoRon was determined by Western Blot. Maximal adiponectin-induced chorionic artery relaxation in LGAs was diminished compared to control. In vitro studies showed no differences in expression of AdipoRs, total AMPK and, eNOS activation between groups; however, higher expression of total eNOS and AMPK activation in HUAEC of LGA relative to AGAs were observed. LGA HUAEC showed diminished NO production and eNOS activity compared to AGA in response to AdipoRon but no changes in AMPK activation. Placental endothelium of LGAs shows a diminished vascular response to adiponectin. Moreover, eNOS activation and adiponectin-dependent NO production is lower in HUAEC of LGA from obese mothers, indicating they present dysfuncional placental-endothelial responses.
Assuntos
Adiponectina/genética , Endotélio Vascular/fisiopatologia , Obesidade/genética , Complicações Cardiovasculares na Gravidez/genética , Quinases Proteína-Quinases Ativadas por AMP , Artérias/metabolismo , Artérias/fisiopatologia , Células Endoteliais/patologia , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Humanos , Recém-Nascido , Masculino , Miografia , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Obesidade/diagnóstico por imagem , Obesidade/metabolismo , Obesidade/fisiopatologia , Placenta/metabolismo , Placenta/fisiopatologia , Circulação Placentária/fisiologia , Gravidez , Complicações Cardiovasculares na Gravidez/metabolismo , Complicações Cardiovasculares na Gravidez/fisiopatologia , Proteínas Quinases/genética , Receptores de Adiponectina/genética , Vasodilatação/genéticaRESUMO
Allele T at promoter region of the eNOS gene has been associated with an increase in coronary disease mortality, suggesting that this allele increases susceptibility for endothelial dysfunction. In contrast, exercise training improves endothelial function. Thus, we hypothesized that: 1) Muscle vasodilatation during exercise is attenuated in individuals homozygous for allele T, and 2) Exercise training improves muscle vasodilatation in response to exercise for TT genotype individuals. From 133 preselected healthy individuals genotyped for the T786C polymorphism, 72 participated in the study: TT (n = 37; age 27 ± 1 yr) and CT+CC (n = 35; age 26 ± 1 yr). Forearm blood flow (venous occlusion plethysmography) and blood pressure (oscillometric automatic cuff) were evaluated at rest and during 30% handgrip exercise. Exercise training consisted of three sessions per week for 18 wk, with intensity between anaerobic threshold and respiratory compensation point. Resting forearm vascular conductance (FVC, P = 0.17) and mean blood pressure (P = 0.70) were similar between groups. However, FVC responses during handgrip exercise were significantly lower in TT individuals compared with CT+CC individuals (0.39 ± 0.12 vs. 1.08 ± 0.27 units, P = 0.01). Exercise training significantly increased peak VO(2) in both groups, but resting FVC remained unchanged. This intervention significantly increased FVC response to handgrip exercise in TT individuals (P = 0.03), but not in CT+CC individuals (P = 0.49), leading to an equivalent FVC response between TT and CT+CC individuals (1.05 ± 0.18 vs. 1.59 ± 0.27 units, P = 0.27). In conclusion, exercise training improves muscle vasodilatation in response to exercise in TT genotype individuals, demonstrating that genetic variants influence the effects of interventions such as exercise training.
Assuntos
Exercício Físico/fisiologia , Músculo Esquelético/irrigação sanguínea , Óxido Nítrico Sintase Tipo III/genética , Vasodilatação/fisiologia , Adolescente , Adulto , Feminino , Genótipo , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Humanos , Masculino , Vasodilatação/genética , Adulto JovemRESUMO
A disfunção endotelial atua tanto na aterogênese como na precipitação das síndromes coronárias agudas. A redução da biodisponibilidade do óxido nítrico é expressão de endotélio disfuncional. O mecanismo desta redução não está elucidado. A presença de disfunção endotelial foi correlacionada com fatores de risco (FR), nitrato sanguíneo e fatores genéticos (polimorfismo do óxido nítrico sintase endotelial / The endothelial dysfunction plays an important roll in the atherogenesis and precipitation of acute coronary syndromes. The reduction of bioavailability of the nitric oxide is the expression of endothelial dysfunction. The exact mechanism of this reduction is not yet well explained. In order to evaluate the presence of endothelial dysfunction and correlation with risk factors (FR), nitrate blood levels and genetic factors (endothelial nitric oxide syntethase polymorphism, fibrinogen and PAI-1) a 128 myocardial infarction patients group with age ≤ 40 year was studied, and underwent a brachial artery ultra-sound. The results were compared with a group of young health individuals...
Assuntos
Adulto , Endotélio/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/análise , Vasodilatação/fisiologia , Artéria Braquial , Vasodilatação/genética , Óxido Nítrico/genéticaRESUMO
El presente trabajo menciona las diversas definiciones de insuficiencia cardíaca y la fisiopatología de esta entidad clínica. Se señalan los objetivos del tratamiento de la insuficiencia cardíaca: la correción de causas subyacentes, la corrección de causas precipitantes, el control de los síntomas y el aumento de la sobrevida. Se analizan cada uno de esos objetivos, especificando las distintas modalidades de corrección de causas subyacentes: prevención y tratamiento de las cardiopatías y de las causas precipitantes. Por último, se discute como los diferentes ensayos terapéuticos modifican la sobrevida de los pacientes con insuficiencia cardíaca a través de mecanismos que llevan a la apoptosis celular