Assuntos
Apolipoproteína B-100/biossíntese , Doença da Artéria Coronariana/metabolismo , Receptor alfa de Estrogênio/biossíntese , Cardiopatias Congênitas/metabolismo , Túnica Íntima/metabolismo , Criança , Pré-Escolar , Doença da Artéria Coronariana/patologia , Feminino , Regulação da Expressão Gênica , Cardiopatias Congênitas/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Lactente , Recém-Nascido , Masculino , Túnica Íntima/patologiaRESUMO
BACKGROUND: A predictor of neonatal mortality in infants with congenital diaphragmatic hernia (CDH) is disrupted pulmonary vascular development, clinically expressed as pulmonary hypertension. OBJECTIVE: To determine if prenatal corticosteroids and phosphodiesterase-5 (PDE-5) inhibitors have a beneficial effect on pulmonary vascular development in CDH lungs. METHODS: We induced CDH in fetal rats by giving nitrofen. We then exposed them to dexamethasone or to sildenafil. We separated them into three groups: (1) DEX, 4 pregnant rats received dexamethasone at days E16, E18 and E20; (2) SILD, 4 pregnant rats received sildenafil and L-arginine between E14 and E22, and (3) placebo. We then analyzed the lung of each fetus with CDH at E22. We examined the number of arterioles and arteries, and their percent of medial wall thickness (%MWT). RESULTS: We obtained 30 CDH-positive fetuses. We analyzed 3,560 arterioles and 211 arteries. SILD showed a significant increase in the number of arterioles, but no significant increase in the number of arteries. No change was noted in the arteriolar %MWT. In contrast, DEX showed significant decreases in the number of arterioles and arteries and a significant increase in %MWT. CONCLUSIONS: PDE-5 inhibitors may improve pulmonary arteriolar development in fetuses with CDH. In contrast, prenatal corticosteroids could have deleterious effects on arteriolar and arterial development in CDH lungs.
Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Hipertensão Pulmonar/prevenção & controle , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Actinas/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Hérnias Diafragmáticas Congênitas/complicações , Hérnias Diafragmáticas Congênitas/fisiopatologia , Hipertensão Pulmonar/etiologia , Imuno-Histoquímica , Neovascularização Fisiológica/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/ultraestrutura , Purinas/farmacologia , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Íntima/ultraestruturaRESUMO
BACKGROUND: Congenital heart defects or the process of their repair leads to an increased risk for adult cardiovascular disease compared with the general population. Intimal hyperplasia is a preatherosclerotic lesion that may be produced as a consequence of transforming growth factor ß1 (TGF-ß1) pathway activation. We studied the presence of intimal hyperplasia in arteries from a pediatric population with congenital heart disease (CHD) and TGF-ß1 expression to enlighten its possible role in the genesis of these lesions. METHODS: Coronary arteries from 10 controls and 98 CHD patients (54% cyanotic type, 32% surgically repaired) were stained, and the presence and degree of intimal thickening were analyzed. The expression of TGF-ß1 was studied by immunohistochemistry. RESULTS: The difference between the presence of coronary intimal hyperplasia in patients with cyanotic (35; 66.1%) and noncyanotic CHD (29; 64.3%) was not significant. However, surgically repaired CHD presented a higher rate of coronary intimal hyperplasia (80%) than did the group without surgical intervention (47.3%), P = 0.0002. The immunostaining for TGF-ß1 analyzed in samples of patients with cyanotic and noncyanotic CHD showed no significant differences. However, TGF-ß1 expression was more intense on the intimal layer of patients with surgically repaired CHD than on that of those without surgery (intimal area positive for TGF-ß1, 50.43% vs 15.91%, respectively; Mann-Whitney U test P = 0.0005). CONCLUSION: The high incidence of intimal hyperplasia in patients with surgically repaired CHD is correlated with TGF-ß1 expression and may contribute to the development of atherosclerotic coronary artery disease in CHD patients.
Assuntos
Vasos Coronários/patologia , Cardiopatias Congênitas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Túnica Íntima/patologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Vasos Coronários/metabolismo , Feminino , Cardiopatias Congênitas/cirurgia , Humanos , Hiperplasia/etiologia , Hiperplasia/metabolismo , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Prevalência , Túnica Íntima/metabolismoRESUMO
The aim of this study was to describe the role of mast cell chymase and tryptase in the progression of atherosclerosis. Forty-four sections of aortas were obtained from autopsies. We assessed the macroscopic degree of atherosclerosis, microscopic intensity of lipid deposition in the tunica intima, percentage of collagen in the tunica intima, and density of immunostained mast cells. There was no significant difference between the density of mast cell tryptase and chymase concerning ethnicity, sex, cause of death, or degree of atherosclerosis. The density of mast cell chymase was significantly higher in the nonelderly group. The percentage of collagen was significantly higher in elderly patients. There was a positive and significant correlation between the degree of macroscopic atherosclerosis and lipidosis, the density of mast cell chymase and the percentage of collagen, the density of mast cell tryptase and the percentage of collagen, and lipidosis and the density of mast cell tryptase. The degree of macroscopic lesion of atherosclerosis increased proportionally with the increase in the density of mast cell chymase and tryptase and in the intensity of lipid deposition and with the percentage of collagen in the atherosclerotic plaques. Thus, mast cells may play a crucial role in aggravating atherosclerotic lesions.
Assuntos
Aterosclerose/metabolismo , Quimases/metabolismo , Progressão da Doença , Mastócitos/enzimologia , Triptases/metabolismo , Adulto , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Autopsia , Colágeno/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
We report a rare case of a congenital left main coronary artery aneurysm in a 2-year-old patient with concomitant intimal hyperplasia and strong intimal apolipoprotein B expression.
Assuntos
Aneurisma Coronário/patologia , Apolipoproteínas B/metabolismo , Pré-Escolar , Aneurisma Coronário/congênito , Angiografia Coronária , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Evolução Fatal , Humanos , Masculino , Tetralogia de Fallot/cirurgia , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
This study aimed to evaluate the effect of rosuvastatin upon structural and ultrastructural aortic remodeling in a rat model of hypertension induced by NO synthase blockade. Wistar rats were divided into 4 groups: Control group (C); control treated with rosuvastatin 20mg/kg/day (CR); L-NAME group 40 mg/kg/day (LN) and L-NAME treated with rosuvastatin (LNR) (same doses). Body mass and blood pressure were measured weekly; the experiment lasted 5 weeks. L-NAME administration augmented blood pressure (BP) in the LN group in comparison to the C group (123.3 vs. 180.5 mm Hg at week 5). In LNR rats, rosuvastatin slightly attenuated BP rise, but it had no effect on the BP of CR group. Intima and media thickening of the thoracic aorta were observed in the LN group, and increased elastic fiber content as well. Rosuvastatin prevented all these alterations as seen in the LNR group. Ultrastructural changes due to L-NAME intake (intracellular vesicles and altered membrane morphology in endothelial cells, extracellular matrix deposition, and cytoplasmatic projections from smooth muscle cells toward the internal elastic lamina) were also prevented by rosuvastatin. All in all, rosuvastatin administration is capable of attenuating ultrastructural aortic wall remodeling in NO-deficient rats despite small changes in blood pressure.
Assuntos
Aorta Torácica/efeitos dos fármacos , Fluorbenzenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão/patologia , Óxido Nítrico/deficiência , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/ultraestrutura , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Fluorbenzenos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Imuno-Histoquímica , Lipídeos/sangue , Microscopia Eletrônica de Transmissão , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Pirimidinas/uso terapêutico , Ratos , Ratos Wistar , Rosuvastatina Cálcica , Sulfonamidas/uso terapêutico , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/ultraestruturaRESUMO
Structural vascular changes in two-kidney, one-clip (2K-1C) hypertension may result from increased matrix metalloproteinase (MMP)-2 activity. MMP-2 activation is regulated by other MMPs, including transmembrane-MMPs, and by tissue inhibitors of MMPs (TIMPs). We have investigated the localization of MMP-2, -9, -14, and TIMPs 1-4 in hypertensive aortas and measured their levels by zymography/Western blotting and immunohistochemistry. Gelatinolytic activity was assayed in tissues by in situ zymography. Sham-operated and 2K-1C hypertensive rats were treated with doxycycline (or vehicle) for 8 weeks, and the systolic blood pressure was monitored weekly. Doxycycline attenuated 2K-1C hypertension (165 + or - 11.7 mmHg versus 213 + or - 7.9 mm Hg in hypertensive controls, P<0.01), and completely prevented increase in the thicknesses of the media and the intima in 2K-1C animals (P<0.01). Increased amounts of MMP-2, -9, and -14 were found in hypertensive aortas, as well as enhanced gelatinolytic activity. A gradient in the localization of MMP-2, -9, and -14 was found, with increased amounts detected in the intima, at sites with higher gelatinolytic activity. Doxycycline attenuated hypertension induced increases in all the 3 investigated MMPs in both the media and the intima (all P<0.05), but it did not change the amounts of TIMPs 1-4 (P>0.05). Therefore, an imbalance between increased amounts of MMPs at the tissue level without a corresponding increase in the quantities of TIMPs, particularly in the intima and inner media layers, appears to account for the increased proteolytic activity found in 2K-1C hypertension-induced maladaptive vascular remodeling.
Assuntos
Matriz Extracelular/metabolismo , Hipertensão/metabolismo , Metaloproteinases da Matriz/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Pressão Sanguínea/fisiologia , Western Blotting , Doxiciclina/farmacologia , Inibidores Enzimáticos/farmacologia , Hipertensão/embriologia , Hipertensão/patologia , Imuno-Histoquímica , Masculino , Tamanho do Órgão/fisiologia , Ratos , Ratos Wistar , Túnica Íntima/metabolismo , Túnica Íntima/ultraestruturaRESUMO
Atherosclerosis is an inflammatory disease of the arterial wall, where both cellular and humoral immunity mechanisms are involved. Vascular endothelial dysfunction and lipoproteins retention into the arterial intima have been reported as the earliest events in atherogenesis, promoting cytokines and chemokines releases; both responsible of leukocytes recruitment. Arterial proteoglycans retain and modify the lipoproteins, increasing their phagocytosis into macrophages through class A and class B scavenger receptors in the case of oxidized lipoproteins (LDLox), causing the production of cytokines like Tumoral Necrosis Factor (TNF)- alpha, Interleukin (IL)-1 beta, IL-6, IL-12 and IL-18, among others. This secretion generates T cells activation into T helper lymphocytes (Th1), able to recognize the LDLox and heat shock protein as autoantigens, amplifying the inflammatory response. Macrophages that have uptaken lipoproteins become foam cells and their accumulation produces the formation of fatty streaks, the first step into atherosclerosis. Due to the biological and clinical importance of these events, the purpose of the present review is to offer recent information on the inflammatory reactions that occur around the establishment of the atheromatous plaque, exhibiting experimental evidences of the physiologic role of leukocytes and their interaction with the extracellular matrix. Furthermore, to emphasize about the major inflammatory biomarkers on the prognosis of cardiovascular diseases.
Assuntos
Aterosclerose/etiologia , Vasculite/complicações , Animais , Aterosclerose/epidemiologia , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Autoantígenos/imunologia , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Quimiocinas/fisiologia , Quimiotaxia de Leucócito , Citocinas/fisiologia , Endotélio Vascular/fisiopatologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Células Espumosas/metabolismo , Células Espumosas/patologia , Proteínas de Choque Térmico/imunologia , Humanos , Lipoproteínas LDL/imunologia , Lipoproteínas LDL/metabolismo , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Camundongos , Músculo Liso Vascular/patologia , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Vasculite/metabolismo , Vasculite/fisiopatologiaRESUMO
BACKGROUND: A gradient of increased vascular risk exists across the African diaspora. We hypothesised that increased insulin resistance with environmental transition contributes to this risk. METHODS: The study was undertaken in 73 healthy African-Caribbeans in the UK and 151 age and sex matched African-Caribbeans in Jamaica. Body mass index (BMI), fasting insulin, insulin resistance, carotid intima media thickness (CIMT) and endothelium dependent vasodilatation (EDV) were compared. CIMT was measured ultrasonographically in the distal 1cm of both common carotid arteries. EDV was measured the absolute change from baseline in the Reflection index (RI) of the digital volume pulse during intravenous infusion of albuterol (DeltaRI(ALB)). RESULTS: UK African-Caribbeans had greater CIMT (mean difference 0.124 [95% C.I. 0.075-0.173] mm, p<0.0001) and decreased EDV (mean difference in DeltaRI(ALB) 5.1 [95% C.I. 2.5-7.6] percentage points, p<0.0001). This was associated with higher insulin concentrations (mean difference 1.6 [95% C.I. 1.3-4.1] microU/mL, p=0.038) and greater HOMA score (2.8 versus 2.0; p=0.035) despite no significant differences in BMI (28.8 versus 27.6; p=0.168) or the waist to hip ratio (0.86 versus 0.85; p=0.188). HOMA scores correlated positively with CIMT (r=0.35, p=0.01) and negatively with DeltaRI(ALB) (r=-0.17; p=0.02) in UK, but not in Jamaican, African-Caribbeans. A significant interaction was seen between HOMA and UK domicile for CIMT (p<0.0001) and between fasting insulin and UK domicile for DeltaRI(ALB) (p<0.0001). CONCLUSIONS: Increased insulin resistance, associated with living in a nutritionally enriched environment, may contribute to early subclinical atherosclerosis in UK African-Caribbeans.
Assuntos
População Negra/estatística & dados numéricos , Doenças das Artérias Carótidas/etnologia , Doenças das Artérias Carótidas/metabolismo , Resistência à Insulina , Agonistas Adrenérgicos beta/administração & dosagem , Adulto , Albuterol/administração & dosagem , Índice de Massa Corporal , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/imunologia , Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Coortes , Meio Ambiente , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Insulina/sangue , Jamaica/epidemiologia , Jamaica/etnologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Túnica Íntima/diagnóstico por imagem , Túnica Íntima/imunologia , Túnica Íntima/metabolismo , Ultrassonografia , Reino Unido/epidemiologia , Vasculite/diagnóstico por imagem , Vasculite/etnologia , Vasculite/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
Arterial sialic acid (SA) has been shown to attenuate the binding of fibrinogen and low-density lipoproteins (LDL) to the vessel wall, presumably protecting against atherosclerosis. This study was aimed to assess the effect of changes in SA content in intimal thickening, an early step in the development of atherosclerosis. New Zealand white rabbits were subjected to bilateral carotid periarterial collaring, followed by in situ-perfusion with neuroaminidase (random artery) and with vehicle (contralateral control artery). The efficiency of SA removal was evaluated in perfusates and arterial homogenates, and arterial tissue samples were obtained 7 and 14 days after the intervention to assess morphological changes. Neuraminidase significantly reduced SA by 16.7%. Arterial desialylation was associated with a significantly increased neointimal formation. Proliferation of smooth muscle cells (SMCs), assessed by incorporation of bromo-2'-deoxyuridine into replicating DNA was also significantly increased in desialylated arteries. In addition, immunohistochemical studies showed a slightly stronger oxidized-LDL (ox-LDL) immunostaining in neointima of desialylated arteries than in control vessels. A mild reduction of SA increases intimal thickening, at least partly due to an enhanced proliferation of SMCs, and may facilitate the accretion of atherogenic lipoproteins, providing evidence for the potential role of SA in the protection against neointimal development.