Age-dependent defective TGF-beta1 signaling in patients undergoing coronary artery bypass grafting.

BACKGROUND: Transforming growth factor beta (TGF-ß1) is a pleiotropic cytokine, which is deregulated in atherosclerosis; however the role of age in this process is unknown. We aimed to assess whether TGF-ß1 signaling is affected by age. METHODS: Vascular smooth muscle cells (VSMC) were obtained from patients undergoing abdominal surgery. Levels of TGF-ß1 were measured by ELISA in sera from 169 patients undergoing coronary artery bypass grafting (CABG). The p27 expression was determined by Western blot from internal mammary arteries (IMA) obtained from CABG patients (n=13). In VSMC from these patients undergoing abdominal surgery, secretion of TGF-ß1 was determined by ELISA of cell-conditioned media. RESULTS: In VSMC from aged patients we observed a lower TGF-ß1 secretion, measured as TGF-ß1 concentration in cell conditioned medium (p<0.001). This effect was correlated to an age-dependent decrease of p27 expression in IMA from aged CABG patients. In a similar manner, there was an age-dependent decrease of serum TGF-ß1 levels in CABG patients (p=0.0195). CONCLUSIONS: VSMC from aged patients showed a higher degree of cellular senescence and it was associated to a lower TGF-ß1 secretion and signaling.

The complex regulation of TGF-ß in cardiovascular disease.

Transforming growth factor ß (TGF-ß1) is a pleiotropic cytokine with many and complex effects in cell and tissue physiology. This is made possible by a very complex and interwoven signaling system, whose regulation continues to be the focus of a growing line of research. This complex regulation translates to a key role in cardiovascular physiology, hemostasis, and the blood-vessel interface. In accordance with this, the TGF-ß1 pathway appears to be deregulated in related disorders, such as atherosclerotic vascular disease and myeloproliferative syndromes. It is expected that the growing amount of experimental and clinical research will yield medical advances in the applications of knowledge of the TGF-ß1 pathway to diagnosis and therapeutics.

Decreased pre-surgical CD34+/CD144+ cell number in patients undergoing coronary artery bypass grafting compared to coronary artery disease-free valvular patients.

BACKGROUND: Cardiovascular disease has been linked to endothelial progenitor cell (EPC) depletion and functional impairment in atherosclerosis and aortic stenosis. EPCs may play a pivotal role in vascular grafting. However, the EPC depletion in coronary artery bypass grafting (CABG) patients has not been compared to coronary artery disease-free valvular replacement patients with aortic stenosis. METHODS: We aimed to assess the basal number of CD34+/KDR+ and CD34+/CD144+ cells in CABG patients, compared to aortic stenosis valvular replacement patients. 100 patients (51 CABG and 49 valvular surgery ones) were included in the present study. All CABG or valvular patients had angiographic demonstration of the presence or the absence of coronary artery disease, respectively. Numbers of CD34+/KDR+ and CD34+/CD144+ were assessed by flow cytometry of pre-surgical blood samples. RESULTS: We found a lower number of CD34+/CD144+ cells in CABG patients compared to valvular patients (0.21 ± 0.03% vs. 0.47 ± 0.08%), and this difference remained statistically significant after the P was adjusted for multiple comparisons (P = 0.01428). Both groups had more EPCs than healthy controls. CONCLUSIONS: Pre-surgical CD34+/CD144+ numbers are decreased in CABG patients, compared to valvular patients with absence of coronary disease.

Pharmacological basis and clinical evidence of dabigatran therapy.

Dabigatran is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. It has been approved in the European Union and the United States of America for the prevention of thrombosis after major orthopedic surgery. It has also been approved by the American Food and Drug Administration and the European Medicines Agency for the prevention of stroke in chronic atrial fibrillation. Dabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, dabigatran may suppose a revolution in oral anticoagulation. However, two important limitations remain. First, it is contraindicated in patients with end-stage renal disease. Second, there is no evidence of the prevention of thrombosis in mechanical heart valves.

Adhesión de células progenitoras endoteliales humanas a arterias humanas de pacientes diabéticos y no diabéticos: efecto de la pioglitazona / Differential adhesion of human endothelial progenitor cells to human arteries from diabetic and non-diabetic patients: effect of pioglitazone

Introducción La disfunción endotelial es un importante mediador de la mayor morbimortalidad cardiovascular de los pacientes diabéticos. Las células progenitoras endoteliales (EPC) parecen poseer defectos funcionales en estos pacientes. La pioglitazona aumenta el número y función de las EPC y disminuye la mortalidad cardiovascular en la población diabética. Objetivos Determinar la capacidad de adhesión de EPC cultivadas sobre arterias de pacientes diabéticos y no diabéticos, así como evaluar los efectos de la glucosa y la pioglitazona sobre estos parámetros. Material y métodos Las EPC se aislaron de células mononucleares a partir de la capa leucoplaquetaria de sangre de donantes y se cultivaron sobre fibronectina en medio microvascular. La adhesión se midió marcando las células con 111In-oxina y pasándolas ex vivo sobre una cámara de flujo con arterias mamarias internas remanentes de cirugía cardiaca. La expresión de la proteína CXCR-4 se determinó por citometría de flujo. Resultados Se observó una mayor adhesión de las EPC sobre las arterias de pacientes diabéticos. Esta adhesión disminuyó al incubar las células con glucosa a 15mM. La co-incubación con pioglitazona 1μM restauró la capacidad adhesiva de las EPC. La glucosa a 15mM disminuyó la expresión de CXCR-4 en las EPC cultivadas, en cambio, la pioglitazona a 1μM fue capaz de aumentarla. Conclusión Pese a que las arterias de pacientes diabéticos tienen una mayor capacidad de reclutar EPC, la hiperglucemia disminuye las propiedades adhesivas de estas células (AU)

Introduction Endothelial dysfunction underlies the increased cardiovascular disease burden in diabetic patients. Endothelial progenitor cell (EPC) function seems to be defective in these patients. Pioglitazone has been shown to improve the number and function of EPCs and to decrease cardiovascular mortality in the diabetic population. Objective To determine the adhesive capacity of cultured EPCs on arteries from diabetic and non-diabetic patients and evaluate the effects of high glucose and pioglitazone on this parameter. Material and methods EPCs were isolated from mononuclear cells from buffy coats, obtained from healthy blood donors. The cells were plated on fibronectin and were cultured in a microvascular medium. EPCs were labelled with 111In-oxine and adhesion was assessed using a flow chamber in which internal mammary arteries obtained from cardiac surgery (..) (AU)

El tratamiento con estatinas mejora las alteraciones ultraestructurales de los vasos oculares en el conejo hipercolesterolémico / Treatment with statins improves the ultrastructural changes of the ocular vessels in hypercholesterolemic rabbits

Introducción Evaluar los cambios ultraestructurales de los vasos coriorretinianos en conejos hipercolesterolémicos tratados con estatinas. Métodos Se utilizaron conejos New Zealand que fueron divididos en 4 grupos: control (G0; n=10), conejos alimentados con una dieta estándar durante 8 meses. Grupo hipercolesterolémico (G1, n=8), conejos alimentados con una dieta enriquecida con 0,5% de colesterol durante 8 meses. Grupo hipercolesterolémico más Fluvastatina sódica (G2A, n=4). Grupo hipercolesterolémico más Pravastatina sódica (G2B, n=4).Métodos Grupo estatinas (G2A y B, n=8), conejos alimentados con una dieta enriquecida con 0,5% de colesterol durante 8 meses más la administración de fluvastatina sódica o pravastatina sódica a una dosis de 2mg/kg/d. Los ojos fueron procesados para microscopía electrónica de trasmisión. Resultados G 1 tenía una gran cantidad de lípidos en la supracoroides que comprimían las capas vasculares coroideas. En G2 las células espumosas y los lípidos de la supracoroides y de las capas vasculares coroideas habían disminuido de forma considerable, aunque había más fibras de colágeno. Las luces de los vasos coroideos estaban más abiertas en G2 que en G1, estando en estos últimos casi colapsadas debido a la compresión y a la hipertrofia de las células musculares lisas y de las células endoteliales. La apariencia normal del endotelio vascular en G2 contrastaba con la necrosis observada en G1. En G2 el espesor de la membrana de Bruch y de las membranas basales de los vasos retinianos y coroideos estaba reducido en comparación con G1. Conclusiones El tratamiento con estatinas reduce la cantidad de lípidos y de macrófagos de la coroides. Además, protege a las células endoteliales y mantiene abiertas las luces de los vasos coroideos (AU)

Introduction To evaluate the ultrastructural changes of the chorioretinal vessels in hypercholesterolemic rabbits after treatment with statins. Methods New Zealand rabbits were divided into four groups: Control (G0; n=10), and fed a standard diet for 8 months; Hypercholesterolemic (G1, n=8), were fed a 0.5% cholesterol-enriched diet for 8 months. Statins group (G2A y B, n=8), were each fed a 0.5% cholesterol-enriched diet for 8 months plus administration of fluvastatin sodium (G2A) or pravastatin sodium (G2B) at a dose of 2mg/Kg/day. Eyes were processed by transmission electron microscopy. Results G1 had a buildup of lipids at the suprachoroidea that compressed the vascular layers. G2 had a substantial decrease in the number of foam cells and lipids but more collagen fibres in the suprachoroidea and vascular layers. The lumen of the choroidal vessels was opened more in G2 in comparison with G1, which had a reduction in the capillary lumen to the point of collapse due to compression and hypertrophy of endothelial and vascular smooth muscle cells. The normal appearance of endothelial cells in G2 was in contrast with the endothelial necrosis observed in G1. In G2, the thickness of the Bruch membrane and the basal membrane of the choroidal and retinal vessels were reduced in comparison with G1. Conclusions Treatment with statins reduces the build up of lipids and the number of macrophages in the choroid. Additionally, they preserve the endothelial cells and open the vascular lumens of choroidal vessels (AU)

Role of TGF-beta1 and MAP kinases in the antiproliferative effect of aspirin in human vascular smooth muscle cells.

BACKGROUND: We aimed to test the antiproliferative effect of acetylsalicylic acid (ASA) on vascular smooth muscle cells (VSMC) from bypass surgery patients and the role of transforming growth factor beta 1 (TGF-beta1). METHODOLOGY/PRINCIPAL FINDINGS: VSMC were isolated from remaining internal mammary artery from patients who underwent bypass surgery. Cell proliferation and DNA fragmentation were assessed by ELISA. Protein expression was assessed by Western blot. ASA inhibited BrdU incorporation at 2 mM. Anti-TGF-beta1 was able to reverse this effect. ASA (2 mM) induced TGF-beta1 secretion; however it was unable to induce Smad activation. ASA increased p38(MAPK) phosphorylation in a TGF-beta1-independent manner. Anti-CD105 (endoglin) was unable to reverse the antiproliferative effect of ASA. Pre-surgical serum levels of TGF-beta1 in patients who took at antiplatelet doses ASA were assessed by ELISA and remained unchanged. CONCLUSIONS/SIGNIFICANCE: In vitro antiproliferative effects of aspirin (at antiinflammatory concentration) on human VSMC obtained from bypass patients are mediated by TGF-beta1 and p38(MAPK). Pre-surgical serum levels of TGF- beta1 from bypass patients who took aspirin at antiplatelet doses did not change.