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1.
Am J Physiol Heart Circ Physiol ; 306(8): H1222-30, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24561861

RESUMO

Patients with pulmonary hypertension associated with congenital heart disease survive longer with preserved right ventricular (RV) function compared with those with primary pulmonary hypertension. The purpose of this study was to test the hypothesis that superior RV performance can be demonstrated, at baseline and when challenged with increased RV afterload, in lambs with chronic left-to-right cardiac shunts compared with control lambs. A shunt was placed between the pulmonary artery and the aorta in fetal lambs (shunt). RV pressure-volume loops were obtained 4 wk after delivery in shunt and control lambs, before and after increased afterload was applied using pulmonary artery banding (PAB). Baseline stroke volume (8.7 ± 1.8 vs. 15.8 ± 2.7 ml, P = 0.04) and cardiac index (73.0 ± 4.0 vs. 159.2 ± 25.1 ml·min(-1)·kg(-1), P = 0.02) were greater in shunts. After PAB, there was no difference in the change in cardiac index (relative to baseline) between groups; however, heart rate (HR) was greater in controls (168 ± 7.3 vs. 138 ± 6.6 beats/min, P = 0.01), and end-systolic elastance (Ees) was greater in shunts (2.63 vs. 1.31 × baseline, P = 0.02). Control lambs showed decreased mechanical efficiency (71% baseline) compared with shunts. With acute afterload challenge, both controls and shunts maintained cardiac output; however, this was via maladaptive responses in controls, while shunts maintained mechanical efficiency and increased contractility via a proposed enhanced Anrep effect-the second, slow inotropic response in the biphasic ventricular response to increased afterload, a novel finding in the RV. The mechanisms related to these physiological differences may have important therapeutic implications.


Assuntos
Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Anastomose Cirúrgica , Animais , Aorta/cirurgia , Cardiomegalia , Modelos Animais de Doenças , Feminino , Hipertensão Pulmonar/fisiopatologia , Contração Miocárdica , Gravidez , Artéria Pulmonar/cirurgia , Ovinos , Volume Sistólico , Função Ventricular Direita , Pressão Ventricular
2.
Am J Physiol Heart Circ Physiol ; 306(7): H954-62, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24531811

RESUMO

We have previously shown decreased pulmonary lymph flow in our lamb model of chronically increased pulmonary blood flow, created by the in utero placement of an 8-mm aortopulmonary shunt. The purpose of this study was to test the hypothesis that abnormal lymphatic function in shunt lambs is due to impaired lymphatic endothelial nitric oxide (NO)-cGMP signaling resulting in increased lymphatic vascular constriction and/or impaired relaxation. Thoracic duct rings were isolated from 4-wk-old shunt (n = 7) and normal (n = 7) lambs to determine length-tension properties, vascular reactivity, and endothelial NO synthase protein. At baseline, shunt thoracic duct rings had 2.6-fold higher peak to peak tension and a 2-fold increase in the strength of contractions compared with normal rings (P < 0.05). In response to norepinephrine, shunt thoracic duct rings had a 2.4-fold increase in vascular tone compared with normal rings (P < 0.05) and impaired relaxation in response to the endothelium-dependent dilator acetylcholine (63% vs. 13%, P < 0.05). In vivo, inhaled NO (40 ppm) increased pulmonary lymph flow (normalized for resistance) ∼1.5-fold in both normal and shunt lambs (P < 0.05). Inhaled NO exposure increased bioavailable NO [nitrite/nitrate (NOx); ∼2.5-fold in normal lambs and ∼3.4-fold in shunt lambs] and cGMP (∼2.5-fold in both) in the pulmonary lymph effluent (P < 0.05). Chronic exposure to increased pulmonary blood flow is associated with pulmonary lymphatic endothelial injury that disrupts NO-cGMP signaling, leading to increased resting vasoconstriction, increased maximal strength of contraction, and impaired endothelium-dependent relaxation. Inhaled NO increases pulmonary lymph NOx and cGMP levels and pulmonary lymph flow in normal and shunt lambs. Therapies that augment NO-cGMP signaling within the lymphatic system may provide benefits, warranting further study.


Assuntos
Cardiopatias Congênitas/metabolismo , Contração Muscular , Relaxamento Muscular , Óxido Nítrico/metabolismo , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Transdução de Sinais , Ducto Torácico/metabolismo , Administração por Inalação , Animais , Velocidade do Fluxo Sanguíneo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Linfático/metabolismo , Endotélio Linfático/fisiopatologia , Cardiopatias Congênitas/fisiopatologia , Linfa/metabolismo , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/farmacologia , Norepinefrina/farmacologia , S-Nitroso-N-Acetilpenicilamina/farmacologia , Ovinos , Transdução de Sinais/efeitos dos fármacos , Ducto Torácico/efeitos dos fármacos , Ducto Torácico/fisiopatologia , Fatores de Tempo
3.
Biochem Biophys Res Commun ; 413(3): 436-41, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21907184

RESUMO

Bone morphogenetic protein-2 (BMP-2) increases oxidant stress and endoplasmic reticulum (ER) stress to stimulate differentiation of osteoblasts; however, the role of these signaling pathways in the transition of smooth muscle cells to a calcifying osteoblast-like phenotype remains incompletely characterized. We, therefore, treated human coronary artery smooth muscle cells (HCSMC) with BMP-2 (100ng/mL) and found an increase in NADPH oxidase activity and oxidant stress that occurred via activation of the bone morphogenetic protein receptor 2 and Smad 1 signaling. BMP-2-mediated oxidant stress also increased endoplasmic reticulum (ER) stress demonstrated by increased expression of GRP78, phospho-IRE1α, and the transcription factor XBP1. Analysis of a 1kb segment of the Runx2 promoter revealed an XBP1 binding site; electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that XBP1 bound to the Runx2 promoter at this site in BMP-2-treated HCSMC. Inhibition of oxidant stress or ER stress decreased Runx2 expression, intracellular calcium deposition, and mineralization of BMP-2-treated HCSMC. Thus, in HCSMC, BMP-2 increases oxidant stress and ER stress to increase Runx2 expression and promote vascular smooth muscle cell calcification.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Calcinose/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Vasos Coronários/patologia , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica , Miócitos de Músculo Liso/patologia , Estresse Oxidativo , Proteína Morfogenética Óssea 2/farmacologia , Calcinose/genética , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Proteínas de Ligação a DNA/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Humanos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a X-Box
4.
Circ Res ; 99(10): 1044-59, 2006 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-17095733

RESUMO

Once thought to result from passive precipitation of calcium and phosphate, it now appears that vascular calcification is a consequence of tightly regulated processes that culminate in organized extracellular matrix deposition by osteoblast-like cells. These cells may be derived from stem cells (circulating or within the vessel wall) or differentiation of existing cells, such as smooth muscle cells (SMCs) or pericytes. Several factors induce this transition, including bone morphogenetic proteins, oxidant stress, high phosphate levels, parathyroid hormone fragments, and vitamin D. Once the osteogenic phenotype is induced, cells gain a distinctive molecular fingerprint, marked by the transcription factor core binding factor alpha1. Alternatively, loss of inhibitors of mineralization, such as matrix gamma-carboxyglutamic acid Gla protein, fetuin, and osteopontin, also contribute to vascular calcification. The normal balance between promotion and inhibition of calcification becomes dysregulated in chronic kidney disease, diabetes mellitus, atherosclerosis, and as a consequence of aging. Once the physiological determinants of calcification are perturbed, calcification may occur at several sites in the cardiovascular system, including the intima and media of vessels and cardiac valves. Here, calcification may occur through overlapping yet distinct molecular mechanisms, each with different clinical ramifications. A variety of imaging techniques are available to visualize vascular calcification, including fluoroscopy, echocardiography, intravascular ultrasound, and electron beam computed tomography. These imaging modalities vary in sensitivity and specificity, as well as clinical application. Through greater understanding of both the mechanism and clinical consequences of vascular calcification, future therapeutic strategies may be more effectively designed and applied.


Assuntos
Calcinose/metabolismo , Doenças Cardiovasculares/metabolismo , Animais , Calcificação Fisiológica , Calcinose/patologia , Doenças Cardiovasculares/patologia , Humanos , Osteogênese/fisiologia
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