RESUMO
Heart failure (HF) with preserved ejection fraction (HFpEF) is a common condition in clinical practice, affecting more than half of patients with HF. HFpEF is associated with morbidity and mortality and with considerable healthcare resource utilization and costs. Therefore, early diagnosis is crucial to facilitate prompt management, particularly initiation of sodium-glucose co-transporter 2 inhibitors. Although European guidelines define HFpEF as the presence of symptoms with or without signs of HF, left ventricular EF ≥ 50%, and objective evidence of cardiac structural and/or functional abnormalities, together with elevated natriuretic peptide levels, the diagnosis of HFpEF remains challenging. First, there is no clear consensus on how HFpEF should be defined. Furthermore, diagnostic tools, such as natriuretic peptide levels and resting echocardiogram findings, are significantly limited in the diagnosis of HFpEF. As a result, some patients are overdiagnosed (i.e., elderly people with comorbidities that mimic HF), although in other cases, HFpEF is overlooked. In this manuscript, we perform a systematic narrative review of the diagnostic approach to patients with HFpEF. We also propose a comprehensible algorithm that can be easily applied in daily clinical practice and could prove useful for confirming or ruling out a diagnosis of HFpEF.
Assuntos
Insuficiência Cardíaca , Idoso , Humanos , Comorbidade , Ecocardiografia , Peptídeos Natriuréticos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
The dynamics of cytoplasmic free Ca2+ concentration ([Ca2+]i) in pancreatic ß cells is central to our understanding of ß-cell physiology and pathology. In this context, there are numerous in vitro studies available but existing in vivo data are scarce. We now critically evaluate the anterior chamber of the eye as an in vivo, non-invasive, imaging site for measuring [Ca2+]i dynamics longitudinally in three dimensions and at single-cell resolution. By applying a fluorescently labeled glucose analogue 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose in vivo, we followed how glucose almost simultaneously distributes to all cells within the islet volume, resulting in [Ca2+]i changes. We found that almost all ß cells in healthy mice responded to a glucose challenge, while in hyperinsulinemic, hyperglycemic mice about 80% of the ß cells could not be further stimulated from fasting basal conditions. This finding indicates that our imaging modality can resolve functional heterogeneity within the ß-cell population in terms of glucose responsiveness. Importantly, we demonstrate that glucose homeostasis is markedly affected using isoflurane compared to hypnorm/midazolam anesthetics, which has major implications for [Ca2+]i measurements. In summary, this setup offers a powerful tool to further investigate in vivo pancreatic ß-cell [Ca2+]i response patterns at single-cell resolution in health and disease.
Assuntos
Cálcio/química , Células Secretoras de Insulina/metabolismo , Anestésicos/farmacologia , Animais , Câmara Anterior/cirurgia , Cálcio/metabolismo , Cruzamentos Genéticos , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Heterozigoto , Homeostase , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Ilhotas Pancreáticas/citologia , Transplante das Ilhotas Pancreáticas , Isoflurano/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Midazolam/farmacologia , FenótipoRESUMO
Although convincing in genetic models, the relevance of ß-cell insulin resistance in diet-induced type 2 diabetes (T2DM) remains unclear. Exemplified by diabetes-prone, male, C57B1/6J mice being fed different combinations of Western-style diet, we show that ß-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased ß-cell workload. Within 8 wk of being fed a high-fat, high-sucrose diet, mice became obese, developed impaired insulin and glucose tolerances, and displayed noncompensatory insulin release, due, at least in part, to reduced expression of syntaxin-1A. Through reporter islets transplanted to the anterior chamber of the eye, we demonstrated a concomitant loss of functional ß-cell mass. When mice were changed from diabetogenic diet to normal chow diet, the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional ß-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet-monitoring approach will allow researchers to define key times in the dynamics of reversible loss of functional ß-cell mass and, thus, to investigate the underlying, molecular mechanisms involved in the progression toward T2DM manifestation.-Paschen, M., Moede, T., Valladolid-Acebes, I., Leibiger, B., Moruzzi, N., Jacob, S., García-Prieto, C. F., Brismar, K., Leibiger, I. B., Berggren, P.-O. Diet-induced ß-cell insulin resistance results in reversible loss of functional ß-cell mass.
Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Resistência à Insulina , Células Secretoras de Insulina/patologia , Insulina/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Resistant albuminuria, developed under adequate chronic blockade of the renin-angiotensin system, is a clinical problem present in a small number of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remains unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal diseases. In the present study we tested the role of MMPs in resistant albuminuria. First we evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Frömter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Markers of oxidative stress were observed in the kidneys of MWF rats, together with a significant increase in pro-MMP-2 and active MMP-9 forms. These changes were normalized together with reduced albuminuria in consomic MWF-8(SHR) rats, in which chromosome 8 of MWF was replaced with the respective chromosome from spontaneously hypertensive rats. The MMP-2 and MMP-9 protein levels were similar in patients with normal and resistant albuminuria; however, high circulating levels of collagen IV, a specific biomarker of tissue collagen IV degradation, were observed in patients with resistant albuminuria. These patients showed a significant increase in gelatinase MMP-2 and MMP-9 activity, but only a significant increase in the active MMP-9 form quantified by ELISA, which correlated significantly with the degree of albuminuria. Although the expression of the tissue inhibitor of MMP-9 (TIMP)-1 was similar, a novel AlphaLISA assay demonstrated that the MMP-9-TIMP-1 interaction was reduced in patients with resistant albuminuria. It is of interest that oxidized TIMP-1 expression was higher in patients with resistant albuminuria. Therefore, increased circulating MMP-9 activity is associated with resistant albuminuria and a deleterious oxidative stress environment appears to be the underlying mechanism. These changes might contribute to the progression of CKD in these patients.
Assuntos
Albuminúria/enzimologia , Rim/enzimologia , Metaloproteinase 9 da Matriz/sangue , Insuficiência Renal Crônica/enzimologia , Idoso , Albuminúria/sangue , Albuminúria/diagnóstico , Albuminúria/genética , Albuminúria/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo , Ligação Proteica , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/prevenção & controle , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-1/sangueRESUMO
Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (-55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (-71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham (P < 0.0008, respectively) and expression decreased significantly in MWF OxTF (P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.
Assuntos
Albuminúria/induzido quimicamente , Orquiectomia/efeitos adversos , Receptores Androgênicos/metabolismo , Caracteres Sexuais , Testosterona/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Estudos de Casos e Controles , Feminino , Flutamida/farmacologia , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Superóxidos/metabolismo , Testosterona/administração & dosagem , Testosterona/sangueRESUMO
Adipose tissue (AT) has become accepted as a source of multipotent progenitor cells, the adipose stromal cells (ASCs). In this regard, considerable work has been performed to harvest and characterize this cell population as well as to investigate the mechanisms by which transplanted ASCs mediate tissue regeneration. In contrast the endogenous release of native ASCs by AT has been poorly investigated. In this work, we show that native ASCs egress from murine AT. Indeed, we demonstrated that the release of native ASCs from AT can be evidenced both using an ex vivo perfusion model that we set up and in vivo. Such a mobilization process is controlled by CXCR4 chemokine receptor. In addition, once mobilized from AT, circulating ASCs were found to navigate through lymph fluid and to home into lymph nodes (LN). Therefore, we demonstrated that, during the LN activation, the fat depot encapsulating the activated LN releases native ASCs, which in turn invade the activated LN. Moreover, the ASCs invading the LN were visualized in close physical interaction with podoplanin and ER-TR7 positive structures corresponding to the stromal network composing the LN. This dynamic was impaired with CXCR4 neutralizing antibody. Taken together, these data provide robust evidences that native ASCs can traffic in vivo and that AT might provide stromal cells to activated LNs.
Assuntos
Tecido Adiposo/citologia , Linfonodos/citologia , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Quimiocina CXCL12/metabolismo , Imunofenotipagem , Linfonodos/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR4/metabolismoRESUMO
Bariatric surgery (BS) results in sustained weight loss and may reverse inflammation, metabolic alterations, extracellular matrix remodeling and arterial stiffness. We hypothesize that increased stiffening in omental arteries from obese patients might be associated with an increase in MMP activity and a decrease in p-AMPK, together with systemic oxidative stress and inflammation. Moreover, BS could contribute to reversing these alterations. This study was conducted with 38 patients of Caucasian origin: 31 adult patients with morbid obesity (9 men and 22 women; mean age 46 years and BMI = 42.7 ± 1.0 kg/m2) and 7 non-obese subjects (7 women; mean age 45 years and BMI = 22.7 ± 0.6 kg/m2). Seventeen obese patients were studied before and 12 months after BS. The stiffness index ß, an index of intrinsic arterial stiffness, was determined in omental arteries and was significantly higher in obese patients. Levels of phosphorylated AMPK (p-AMPKThr-172) and SIRT-1 were significantly lower in peripheral blood mononuclear cells (PBMCs) from obese patients than those from non-obese patients (p < 0.05) and were normalized after BS. Total and active MMP-9 activities, LDH, protein carbonyls and uric acid were higher in obese patients and reduced by BS. Moreover, there was a correlation between plasmatic LDH levels and the stiffness index ß. BS has a beneficial effect on abnormal MMP-9, LDH and AMPK activities that might be associated with the development of arterial stiffness in obese patients. Since these parameters are easily measured in blood samples, they could constitute potential biomarkers of cardiovascular risk in morbid obesity.
RESUMO
Caloric restriction (CR) improves endothelial function through the upregulation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, hydrogen peroxide (H2O2) is upregulated in yeast subjected to CR. Our aim was to assess if mild short-term CR increases vascular H2O2 formation as a link with AMPK and eNOS activation. Twelve-week old Zucker obese (fa/fa) and control Zucker lean male rats were fed a standard chow either ad libitum (AL, n=10) or with a 20% CR (CR, n=10) for two weeks. CR significantly improved relaxation to ACh in fa/fa rats because of an enhanced endogenous production of H2O2 in aortic rings (H2O2 levels fa/faAL=0.5⯱â¯0.05â¯nmol/mg vs. H2O2 levels fa/faCR=0.76⯱â¯0.07â¯nmol/mg protein; p<0.05). Expression of mitochondrial superoxide dismutase (Mn-SOD) and total SOD activity were increased in aorta from fa/fa animals after CR. In cultured aortic endothelial cells, serum deprivation or 2-deoxy-d-glucose induced a significant increase in: i) superoxide anion and H2O2 levels, ii) p-AMPK/AMPK and p-eNOS/eNOS expression and iii) nitric oxide levels. This effect was reduced by catalase and strongly inhibited by Ca2+/calmodulin-dependent kinase II (CamkII) silencing. In conclusion, we propose that mild short-term CR might be a trigger of mechanisms aimed at protecting the vascular wall by the increase of H2O2, which then activates AMPK and nitric oxide release, thus improving endothelium-dependent relaxation. In addition, we demonstrate that CAMKII plays a key role in mediating CR-induced AMPK activation through H2O2 increase.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Restrição Calórica , Peróxido de Hidrogênio/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Obesidade/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Catalase/genética , Catalase/metabolismo , Desoxiglucose/farmacologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Zucker , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , VasodilataçãoRESUMO
Background Hypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow-associated shear stress. Ryanodine receptors (RyRs) are major Ca2+-release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen-inducible smooth muscle cell-specific RyR2-deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow. Methods and Results Targeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum-mediated Ca2+-release events and associated Ca2+-activated, large-conductance K+ channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow-dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected. Conclusions Our results establish that RyR2-mediated Ca2+-release events in VSCM s specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell-expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.
Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Artérias/metabolismo , Artérias/fisiopatologia , Pressão Sanguínea/fisiologia , Sinalização do Cálcio , Membro Posterior/irrigação sanguínea , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Fluxometria por Laser-Doppler , Pulmão/irrigação sanguínea , Camundongos , Camundongos Knockout , Músculo Liso Vascular/fisiopatologia , Miografia , Técnicas de Patch-Clamp , Inibidores de Fosfodiesterase/farmacologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , VasoconstriçãoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.
Assuntos
Ilhotas Pancreáticas/ultraestrutura , Comunicação Parácrina , Estado Pré-Diabético/patologia , Pseudópodes/ultraestrutura , Células Secretoras de Somatostatina/ultraestrutura , Animais , Glicemia/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/ultraestrutura , Microscopia Intravital , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Imagem Óptica , Optogenética , Estado Pré-Diabético/metabolismo , Pseudópodes/metabolismo , Células Secretoras de Somatostatina/citologia , Células Secretoras de Somatostatina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30-65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile.
RESUMO
BACKGROUND AND AIMS: Fetal undernutrition is a risk factor for heart disease in both genders, despite the protection of women against hypertension development. Using a rat model of maternal undernutrition (MUN) we aimed to assess possible sex differences in the development of cardiac alterations and the implication of hypertension and cardiac oxidative stress. METHODS: Male and female offspring from rats fed ad libitum (control) or with 50% of the normal daily intake during the second half of gestation (MUN) were used. Heart weight/body weight ratio (HW/BW), hemodynamic parameters (anaesthetized rats) and plasma brain natriuretic peptide (BNP, ELISA) were assessed in 21-day, 6-month and 22-month old rats. Plasma testosterone (ELISA) and cardiac protein expression of enzymes related to reactive oxygen species synthesis (p22phox, xanthine-oxidase) and degradation (catalase, Cu/Zn-SOD, Mn-SOD, Ec-SOD) were evaluated in 21-day and 6-month old rats (Western Blot). Heart structure and function was studied at the age of 22 months (echocardiography). RESULTS: At the age of 21 days MUN males exhibited significantly larger HW/BW and cardiac p22phox expression while females had reduced p22phox expression, compared to their respective sex-matched controls. At the age of 6-months, MUN males showed significantly larger blood pressure and cardiac xanthine-oxidase expression; MUN females were normotensive and had a lower cardiac expression of antioxidant enzymes, compared to their respective sex-matched controls. At the age of 22 months, both MUN males and females showed larger HW/BW and left ventricular mass and lower ejection fraction compared to sex-matched controls; only MUN males exhibited hypertension and a larger plasma BNP compared to aged male controls. CONCLUSIONS: 1) During perinatal life females exposed to fetal undernutrition are protected from cardiac alterations, but in ageing they exhibit ventricular hypertrophy and functional loss, like MUN males; 2) cardiac oxidative stress might be implicated in the observed heart alterations in both sexes and 3) the severity of cardiac damage might be greater in males due to hypertension.
Assuntos
Transtornos da Nutrição Fetal , Hipertensão/metabolismo , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Peso Corporal , Feminino , Hemodinâmica , Hormônios/sangue , Hipertensão/sangue , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Mães , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Caracteres Sexuais , Fatores de TempoRESUMO
Caloric restriction (CR) has proved to be the most effective and reproducible dietary intervention to increase healthy lifespan and aging. A reduction in cardiovascular disease (CVD) risk in obese subjects can be already achieved by a moderate and sustainable weight loss. Since pharmacological approaches for body weight reduction have, at present, a poor long-term efficacy, CR is of great interest in the prevention and/or reduction of CVD associated with obesity. Other dietary strategies changing specific macronutrients, such as altering carbohydrates, protein content or diet glycemic index have been also shown to decrease the progression of CVD in obese patients. In this review, we will focus on the positive effects and possible mechanisms of action of these strategies on vascular dysfunction.
Assuntos
Envelhecimento , Restrição Calórica , Doenças Cardiovasculares/prevenção & controle , Doenças Metabólicas/prevenção & controle , Animais , Peso Corporal , Doenças Cardiovasculares/etiologia , Dieta Redutora , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Modelos Animais de Doenças , Ingestão de Energia , Índice Glicêmico , Humanos , Doenças Metabólicas/etiologia , Obesidade/complicações , Obesidade/dietoterapia , Fatores de RiscoRESUMO
SCOPE: Activation of endothelial adenosine monophosphate-activated protein kinase (AMPK) contributes to increase nitric oxide (NO) availability. The aim of this study was to assess if high-fat diet (HFD)-induced endothelial dysfunction is linked to AMPK deregulation. METHODS AND RESULTS: Twelve-week-old Sprague Dawley male rats were assigned either to control (10 kcal % from fat) or to HFD (45 kcal % from fat) for 8 wk. HFD rats segregated in obesity-prone (OP) or obesity-resistant (OR) rats according to body weight. HFD triggered an impaired glucose management together with impaired endothelium-dependent relaxation, reduced endothelial AMPK activity and lower NO availability in aortic rings of OP and OR cohorts. Relaxation evoked by AMPK activator, 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR) was reduced in both OP and OR rings, which exhibited lower p-AMPKα-Thr(172) /AMPKα ratios that negatively correlated with plasma non-esterified fatty acids (NEFA) and triglycerides (TG). Inhibition of PI3K (wortmannin, 10(-7) M) or Akt (triciribine, 10(-5) M) reduced relaxation to AICAR only in the control group (p < 0.001). Akt (p-Akt-Ser(473) ) and eNOS phosphorylation (p-eNOS-Ser(1177) ) were significantly reduced in OP and OR (p < 0.01). CONCLUSION: Endothelial dysfunction caused by HFD is related to a dysfunctional endothelial AMPK-PI3K-Akt-eNOS pathway correlating with the increase of plasma NEFA, TG, and an impaired glucose management.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Regulação para Baixo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: The hypothesis of this study is that long-term high-fat diets (HFD) induce perivascular adipose tissue (PVAT) dysfunction characterized by a redox imbalance, which might contribute to aggravate endothelial dysfunction in obesity. METHODS AND RESULTS: C57BL/6J mice were fed either control or HFD (45% kcal from fat) for 32 weeks. Body weight, lumbar and mesenteric adipose tissue weights were significantly higher in HFD animals compared to controls. The anticontractile effect of PVAT in mesenteric arteries (MA) was lost after 32 week HFD and mesenteric endothelial-dependent relaxation was significantly impaired in presence of PVAT in HFD mice (Emaxâ=â71.0±5.1 vs Emaxâ=â58.5±4.2, p<0.001). The inhibitory effect of L-NAME on Ach-induced relaxation was less intense in the HFD group compared with controls suggesting a reduction of endothelial NO availability. Expression of eNOS and NO bioavailability were reduced in MA and almost undetectable in mesenteric PVAT of the HFD group. Superoxide levels and NOX activity were higher in PVAT of HFD mice. Apocynin only reduced contractile responses to NA in HFD animals. Expression of ec-SOD and total SOD activity were significantly reduced in PVAT of HFD mice. No changes were observed in Mn-SOD, Cu/Zn-SOD or catalase. The ratio [GSSG]/([GSH]+[GSSG]) was 2-fold higher in the mesenteric PVAT from HFD animals compared to controls. CONCLUSIONS: We suggest that the imbalance between pro-oxidant (NOX, superoxide anions, hydrogen peroxide) and anti-oxidant (eNOS, NO, ecSOD, GSSG) mechanisms in PVAT after long-term HFD might contribute to the aggravation of endothelial dysfunction.
Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Animais , Peso Corporal/fisiologia , Peróxido de Hidrogênio/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Superóxidos/metabolismoRESUMO
Most blood vessels are surrounded by adipose tissue. Similarly to the adventitia, perivascular adipose tissue (PVAT) was considered only as a passive structural support for the vasculature, and it was routinely removed for isolated blood vessel studies. In 1991, Soltis and Cassis demonstrated for the first time that PVAT reduced contractions to noradrenaline in rat aorta. Since then, an important number of adipocyte-derived factors with physiological and pathophysiological paracrine vasoactive effects have been identified. PVAT undergoes structural and functional changes in obesity. During early diet-induced obesity, an adaptative overproduction of vasodilator factors occurs in PVAT, probably aimed at protecting vascular function. However, in established obesity, PVAT loses its anticontractile properties by an increase of contractile, oxidative, and inflammatory factors, leading to endothelial dysfunction and vascular disease. The aim of this review is to focus on PVAT dysfunction mechanisms in obesity.
RESUMO
OBJECTIVE: The Munich Wistar Frömter (MWF) rat develops progressive spontaneous albuminuria largely attributable to quantitative trait loci on rat chromosome (RNO)6 and RNO8, respectively. We tested the hypothesis whether quantitative trait loci on these chromosomes are linked to both albuminuria and endothelial dysfunction. METHODS: Experiments were performed in male 12-week-old MWF, Wistar Kyoto (WKY), spontaneously hypertensive rat (SHR) and consomic MWF-6 and MWF-8 rats, in which RNO6 or RNO8 was replaced by the respective SHR chromosome (nâ=â10 per strain). Vascular function was assessed in aorta and vascular superoxide anion production was determined by confocal microscopy. RESULTS: Acetylcholine potency to induce relaxation was significantly reduced in MWF (6.2â±â0.1) compared with WKY (7.1â±â0.1) or SHR (7.3â±â0.1; Pâ<â0.01). N-nitro-L-arginine methyl ester abolished relaxation to acetylcholine in all three strains, whereas indomethacin exhibited no effect in WKY and MWF. Contractions to noradrenaline and superoxide production were significantly higher in MWF compared with SHR and WKY (Pâ<â0.05, respectively). In consomic MWF-6 and MWF-8 rats albuminuria was markedly suppressed (-85 and -92%, Pâ<â0.005 compared with MWF, respectively). Interestingly, relaxation to acetylcholine and contraction to noradrenaline were restored to normal WKY levels only in MWF-8, but not in MWF-6, due to an increase in stimulated and basal nitric oxide availability, respectively. CONCLUSION: These data demonstrate the partial genetic independence of albuminuria and endothelial dysfunction in this model. From two known albuminuria quantitative trait loci one locus affects both albuminuria and endothelial dysfunction. Whether this observation is based on a common genetic mechanism related to NO availability warrants further investigation.
Assuntos
Albuminúria/genética , Predisposição Genética para Doença , Locos de Características Quantitativas , Acetilcolina/antagonistas & inibidores , Acetilcolina/farmacologia , Albuminúria/fisiopatologia , Animais , Aorta/fisiopatologia , Arginina/análogos & derivados , Arginina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Indometacina/farmacologia , Masculino , Óxido Nítrico/genética , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Superóxidos/metabolismo , Doenças VascularesRESUMO
Leptin causes vasodilatation both by endothelium-dependent and -independent mechanisms. Leptin is synthesized by perivascular adipose tissue (PVAT). The hypothesis of this study is that a decrease of leptin production in PVAT of spontaneously hypertensive rats (SHR) might contribute to a diminished paracrine anticontractile effect of the hormone. We have determined in aorta from Wistar-Kyoto (WKY) and SHR (i) leptin mRNA and protein levels in PVAT, (ii) the effect of leptin and PVAT on contractile responses, and (iii) leptin-induced relaxation and nitric oxide (NO) production. Leptin mRNA and protein expression were significantly lower in PVAT from SHR. Concentration-response curves to angiotensin II were significantly blunted in presence of PVAT as well as by exogenous leptin (10(-9) M) only in WKY. This anticontractile effect was endothelium-dependent. Vasodilatation induced by leptin was smaller in SHR than in WKY, and was also endothelium-dependent. Moreover, release of endothelial NO in response to acute leptin was higher in WKY compared to SHR, but completely abolished in the absence of endothelium. In conclusion, the reduced anticontractile effect of PVAT in SHR might be attributed to a reduced PVAT-derived leptin and to an abrogated effect of leptin on endothelial NO release probably due to an impaired activation of endothelial NO synthase.