Inflammation has a pivotal role in the development of atherosclerosis and acute activation of the vascular wall with consecutive local thrombosis and altered vasomotion. This process is orchestrated by the interactions between inflammatory cells, such as platelets and T and B lymphocytes, and vascular cells, endothelial cells, and smooth muscle cells. When they are activated by an agonist, shear stress, or apoptosis, these cells release vesicles shed from the blebbing plasma membrane called microparticles. Microparticles harbor cell surface proteins and contain cytoplasmic components of the original cell. They exhibit negatively charged phospholipids, chiefly phosphatidylserine, at their surface, which accounts for their procoagulant character and proinflammatory properties, including alteration of vascular function. Elevated levels of circulating microparticles have been detected in pathological states associated with vascular dysfunction, including attenuation of endothelium-dependent vasodilatation and/or alteration of responsiveness of vascular smooth muscle to vasoconstrictor stimuli in conductance and resistance arteries. This review points out the characteristics of microparticles as well as the biological messages they can mediate. In particular, it summarizes the signaling cascades involved in microparticle-induced vascular dysfunction with special attention to the cellular origin of these vesicles (platelet, endothelial, and leukocytic), which may explain their differential consequences on vascular remodeling. The available information provides a rationale for the paracrine role of microparticles as vectors of transcellular exchange of message between circulating cells and cells from the vascular wall.
Microparticles are membrane vesicles that are released during cell activation and apoptosis. Elevated levels of microparticles occur in many cardiovascular diseases; therefore, we characterized circulating microparticles from both metabolic syndrome (MS) patients and healthy patients. We evaluated microparticle effects on endothelial function; however, links between circulating microparticles and endothelial dysfunction have not yet been demonstrated. Circulating microparticles and their cellular origins were examined by flow cytometry of blood samples from patients and healthy subjects. Microparticles were used either to treat human endothelial cells in vitro or to assess endothelium function in mice after intravenous injection. MS patients had increased circulating levels of microparticles compared with healthy patients, including microparticles from platelet, endothelial, erythrocyte, and procoagulant origins. In vitro treatment of endothelial cells with microparticles from MS patients reduced both nitric oxide (NO) and superoxide anion production, resulting in protein tyrosine nitration. These effects were associated with enhanced phosphorylation of endothelial NO synthase at the site of inhibition. The reduction of O 2 ؊ was linked to both reduced expression of p47 phox of NADPH oxidase and overexpression of extracellular superoxide dismutase. The decrease in NO production was triggered by nonplatelet-derived microparticles. In vivo injection of MS microparticles into mice impaired endothelium-dependent relaxation and decreased endothelial NO synthase expression. These data provide evidence that circulating microparticles from MS patients influence endothelial dysfunction. (Am J Pathol
Incidence rates of oral and oropharyngeal cancers (oral cancer) in Spain are among the highest in Europe. Spain has a population heavily exposed to various types of tobacco and alcoholic beverages but the role and impact of tobacco type and beverage type in oral carcinogenesis remain controversial. To estimate the independent and joint effects of tobacco smoking and alcohol drinking habits on the risk of developing oral cancer, we carried out a multicenter, hospital-based, case-control study in Spain. Data from 375 patients newly diagnosed with cancer of the oral cavity or oropharynx and 375 matched control subjects were analyzed using multivariate logistic regression procedures. All exposure characteristics of amount, duration and cessation of both tobacco smoking and alcohol drinking were strongly associated with cancer risk following a dose-dependent relationship. At equal intake or duration levels, black-tobacco smoking and drinking of spirits were both associated with a 2-to 4-fold increase in cancer risk compared to blond tobacco smoking or drinking of wine or beer, respectively. While ever exposure to smoking only or drinking only was associated with a moderate and nonsignificant increase in cancer risk, a history of simultaneous exposure to both habits was associated with a 13-fold increase that was compatible with a synergistic effect model (p-value for interaction: 0.008). Exposure to black tobacco smoking and/or drinking of spirits may account for up to 77% of oral cancer occurrence in Spain. Both black tobacco smoking and drinking of spirits place individuals at a very high risk of developing oral cancer. Simultaneous exposure to tobacco and alcohol consumption increases oral cancer risk in a synergistic fashion, even when consumption levels are moderate. These results underline the importance of type of tobacco and alcohol concentration in oral carcinogenesis. © 2003 Wiley-Liss, Inc. Key words: tobacco; alcohol; oral cavity; oropharynx; neoplasiaCancer of the oral cavity and pharynx (oral cancer) is a major and increasing public health problem in Europe. Spain, with a European age-adjusted incidence rate of 31.4 per 100,000 men per year, 1 is, after France, the European country with the second highest incidence rate for these cancer sites.These tumors are prominent among middle-aged adults, and increasing rates are occurring mainly among young and middleaged men. Population-based screening and early detection programs are rare or nonexistent, and in spite of surgical advances, these cancers remain a disfiguring disease associated with a relatively low survival rate. 2,3 Tobacco smoking and alcohol drinking have long and consistently been identified as the 2 major risk factors for oral cancer in most Western populations. 4 -6 Other risk factors that play a role include diets low in fruits and vegetables, 7,8 family history of cancer 9,10 and, to a lesser extent, infection by oncogenic human papillomaviruses (HPV). [11][12][13] Despite the clear role of tobacco and alcohol consumption in the etiology...
Background-Microparticles (MPs) are membrane vesicles with procoagulant and proinflammatory properties released during cell activation. The present study was designed to dissect the effects evoked by T lymphocyte-derived MPs on vascular function. Methods and Results-MPs were produced by treatment of the human lymphoid CEM T cell line with actinomycin D or phytohemagglutinin. Incubation of mouse aortic rings with 30 nmol/L MPs resulted in a time-dependent impairment of acetylcholine-induced relaxation of precontracted vessels, with a maximal reduction after 24 hours. MPs also impaired shear stress-induced dilatation of mouse small mesenteric arteries by affecting the nitric oxide (NO) and prostacyclin but not the endothelium-derived hyperpolarizing factor components of the response. However, neither alteration of calcium signaling in response to agonists nor reduction of cyclooxygenase-1 expression accounted for the impairment of the NO and prostacyclin components of the endothelial response. The effect of MPs was rather because of a decrease in expression of endothelial NO synthase and an overexpression of caveolin-1. Furthermore, lymphocyte-derived MPs from diabetic patients or in vivo circulating MPs from either diabetic or HIV-infected patients reduced endothelial NO synthase expression. Finally, the effects of MPs on endothelial cells were not driven through CD11a/CD18 adhesion molecules or the Fas/FasL pathway. Conclusions-MPs from T cells induce endothelial dysfunction in both conductance and resistance arteries by alteration of NO and prostacyclin pathways. MPs regulate protein expression for endothelial NO synthase and caveolin-1. These data contribute to a better understanding of the deleterious effects of enhanced circulating MPs observed in disorders with cardiovascular or immune complications.
Microparticles (MPs) are small fragments generated from the plasma membrane after cell stimulation. Among the candidate proteins harbored by MPs, we recently showed that sonic hedgehog (Shh) is present in MPs generated from activated/apoptotic human T lymphocytes [Martínez et al., Blood (2006) vol. 108, 3012-3020]. We show here that Shh carried by MPs induces nitric oxide (NO) release from endothelial cells, triggers changes in the expression and phosphorylation of enzymes related to the NO pathway, and decreases production of reactive oxygen species. When PI3-kinase and ERK signaling were specifically inhibited, the effects of MPs were reversed. In vivo injection of MPs in mice was also able to improve endothelial function by increasing NO release, and it reversed endothelial dysfunction after ischemia/reperfusion. Silencing the effects of Shh with cyclopamine, a specific inhibitor of Shh, or siRNA, an inhibitor of the Shh receptor Patched, strongly reduced production of NO elicited by MPs. Taken together, we propose that the biological message carried by MPs harboring Shh may represent a new therapeutic approach against endothelial dysfunction during acute severe endothelial injury.
Introduçãosatisfação no trabalho é um fenômeno amplamente estudado e esse interesse decorre da influência que a mesma pode exercer sobre o trabalhador, afetando sua saúde física e mental, atitudes, comportamento profissional, social, tanto com repercussões para a vida pessoal e familiar do indivíduo como para as organizações (Cura, 1994;Locke, 1976;Pérez-Ramos, 1980;Zalewska 1999aZalewska , 1999b.Os estudos sistematizados sobre satisfação no trabalho iniciaram-se na década de 30 (Klijn, 1998) e desde então têm despertado o interesse de profissionais de saúde e de pesquisadores das mais diversas áreas.Ainda não há consenso sobre conceitos nem sobre teorias ou modelos teóricos de satisfação no trabalho. Além disso, diferentes conceitos e definições para o mesmo construto têm gerado dificuldades e até mesmo falhas metodológicas em estudos sobre o tema (Cura, 1994;Pérez-Ramos, 1980). Apesar de relevante e freqüentemente mencionada, a relação entre satisfação no trabalho e saúde tem sido insuficientemente pesquisada e aplicada (Martinez, 2002). O conhecimento sistematizado sobre a maneira como se configuram e os resultados das relações entre satisfação e saúde são relevantes, tanto para auxiliar no estabelecimento de um
Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances.Key words: Polyphenols: Cardiovascular system: Nitric oxide: Endothelium: Free radicals: Antioxidants Polyphenols are found mainly in plant-derived foods and beverages, and provide the tastes and colour of plant foods while also participating in plant defensive responses against stress due to UV radiation, pathogens and physical damage. There are a number of excellent reviews dealing with their protective effect against cancers, cardiovascular, metabolic (1) and neurodegenerative diseases (2) . The structures of polyphenols vary from a simple phenol core to complex molecules with a high degree of polymerisation. This family can be divided into simple phenols, flavonoids and non-flavonoids such as stilbene (resveratrol), saponin, curcumin and tannins.
Microparticles (MPs) are small fragments generated from the plasma membrane after cell stimulation or apoptosis. We have recently shown that MPs harboring the morphogen Sonic Hedgehog (MPs(Shh+)) correct endothelial injury by release of nitric oxide from endothelial cells [Agouni, Mostefai, Porro, Carusio, Favre, Richard, Henrion, Martínez and Andriantsitohaina (2007) FASEB J., 21, 2735-2741]. Here, we show that MPs(Shh+) induce the formation of capillary-like structures in an in vitro model using human endothelial cells, although they inhibited cell migration. Besides, MPs(Shh+) regulate cell proliferation. Both cell adhesion and expression of proteins involved in this process such as Rho A and phosphorylation of focal-activated kinase were increased by MPs(Shh+), via a Rho-associated coiled-coil-containing protein kinase inhibitor-sensitive pathway. We demonstrate that MPs(Shh+) increase messenger RNA and protein levels of proangiogenic factors as measured by quantitative reverse transcription-polymerase chain reaction and western blot. In spite of vascular endothelial growth factor expression, conditioned media from endothelial cells treated avec MPs(Shh+) reduces angiogenesis. Interestingly, the effects induced by MPs(Shh+) on the formation of capillary-like structures, expression of adhesion molecules and proangiogenic factors were reversed after silencing of the Shh receptor, using small interfering RNA or when Sonic Hedgehog (Shh) signaling was pharmacologically inhibited with cyclopamine. Taken together, we show that Shh carried by MPs(Shh+) regulate angiogenesis probably through both a direct and an indirect mechanisms, and we propose that MPs harboring Shh may contribute to the generation of a vascular network in pathologies associated with tumor growth.
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