Hydrogen sulfide (H2S) is an endogenous gasotransmitter that regulates vascular function and blood pressure, and also protects the heart from injury associated with myocardial infarction (MI). The mitochondrial enzyme thiosulfate sulfurtransferase (TST) has a putative role in the breakdown of H2S but its role in the cardiovascular system is unknown. I hypothesised that TST reduces cardiovascular H2S availability and that inhibiting TST activity may therefore ameliorate cardiovascular pathology. In the heart, TST was expressed by cardiomyocytes and vascular smooth muscle cells. Tst-/- mice all survived to adulthood and had normal cardiac structure and function. Cardiac and hepatic H2S breakdown rates were reduced and H2S levels were higher in the blood of Tst-/- mice. However, in heart tissue, protein levels for the H2S-activated Nrf2 downstream targets, thioredoxin (Trx1) and heme oxygenase-1 (HO-1) were comparable. In contrast, protein levels for the cardiac specific H2S-synthetic enzyme, cystathionine gamma lyase (CSE) was reduced, suggesting a homeostatic negative feedback mechanism to maintain H2S at non-toxic levels. Respiration, measured using an oxygen-sensing electrode was normal in isolated mitochondria from whole Tst-/- compared to control C57BL6 hearts. Endothelial nitric oxide synthase (eNOS) protein expression was lower in Tst-/- hearts, highlighting potential cross talk between H2S and nitric oxide (NO) signalling. TST was expressed in whole aorta homogenates and in isolated endothelial cells from aorta and small intramuscular vessels of the hindlimb from C57BL/6N control mice. Myography and western blotting revealed a greater influence of NO in aorta from Tst-/- mice that was associated with increased phosphorylation of the activating serine1177 residue of eNOS (PeNOSSer1177). NO plays a lesser role in resistance arteries, but in comparison to control vessels, small mesenteric vessels from Tst-/- mice was more reliant on small and intermediate calcium activated potassium channels for relaxation. Tst-/- mice were normotensive, despite this alteration in the regulation of vascular tone. However, metabolic cage experiments identified that Tst-/- mice presented with diuresis, polydipsia, and increased urinary electrolyte excretion of sodium, potassium and chloride, possibly to compensate for increased vascular tone in order to maintain stable blood pressure. To investigate the role of TST in regulating the response to pathological challenge, MI was induced by coronary artery ligation (CAL). In control mice, gene expression of CSE was downregulated by 2 days after CAL, but TST expression was 12-fold increased, suggesting regulation of H2S bioavailability during the acute MI-healing phase. Tst-/- male mice had a 40% greater incidence of cardiac rupture during infarct healing and surviving Tst-/- mice had greater left ventricular dilatation and impaired function compared to controls. Ex vivo, isolated perfused hearts from Tst-/- mice were more susceptible to ischaemia/ reperfusion injury, suggesting an additional role of TST in determining cardiomyocyte susceptibility to injury. In conclusion, these data indicate that cardiovascular H2S bioavailability is regulated through degradation by TST. The data presented here provide evidence for significant tissue specific crosstalk between H2S synthetic and degradative mechanisms and between H2S and other local regulatory mechanisms, including ion channels and NOS. We infer TST has a physiological role in the kidney where its loss leads to changes in renal electrolyte and water handling, although other compensatory mechanisms prevent a change in blood pressure. Under conditions of pathological challenge following MI, loss of TST is detrimental, illustrating its key role in removal of H2S. The data refute the original hypothesis that TST inhibition would be protective against cardiovascular pathology. Further studies in mice with tissue specific deletion of TST are now required to more fully reveal the cardiovascular role of TST.

Bakgrund: I Sverige är hjärt- kärl sjukdomar den vanligaste dödsorsaken, år 2016 drabbades 25 700 individer av en akut hjärtinfarkt. Efter att ha drabbats av en hjärtinfarkt medför detta förändringar i kroppen och återhämtningsprocessen kan ta tid. För att bemöta dessa patienter med en individanpassad vård behöver sjuksköterskan ha kunskap om vad som påverkar dessa patienter under återhämtningsprocessen och på så sätt hjälpa patienten i deras behov. Syfte: Syftet var att belysa patientens upplevelser och erfarenheter av att ha drabbats av hjärtinfarkt upp till ett år efter insjuknandet. Metod: En litteraturöversikt där tio kvalitativa artiklar från PsychINFO, PubMed och Cinahl complete har granskats och analyserats. Resultat: I denna litteraturöversikt framkommer tre teman: patientens upplevelser som helhet, behovet av stöd samt ett förändrad syn på livet. I dessa teman beskrivs patienternas upplevelser och erfarenheter av att ha drabbats av hjärtinfarkt samt vilka utmaningar de möter i vardagliga livet. Diskussion: Patienterna möter olika utmaningar i det vardagliga livet efter att ha drabbats av hjärtinfarkt. Dessa förändringar kan upplevas som utmaningar och medförde frånvaro av välbefinnande och hälsa. Det är inte bara kroppen som påverkas och behöver behandling, patienter som drabbas av hjärtinfarkt påverkas psykiskt och fysiskt. Teoretikern Katie Eriksson menar att människan består av kropp, själ och ande vilket  utgör kärnan för hälsoprocessen. Många patienter upplever oro och rädsla av att återigen drabbas av ny hjärtinfarkt. Resultatet visade på betydelsen av att bli informera av sjuksköterskan om vilka utmaningar som patienten möjligen kan möta, rehabiliteringens betydelse, symtom, samt vilka livsstilsförändringar som kan ha positiv påverkan på hälsan och välbefinnandet.

Coronary atherosclerosis and plaque rupture leads to acute coronary thrombosis and myocardial infarction. Current treatment involves re-establishing vessel patency, but no treatments have been developed to target post-infarction inflammatory pathways. Such treatments may reduce cardiomyocyte injury, attenuate adverse remodelling and improve clinical outcome. Inflammation within the infarcted myocardium is associated with chemotaxis of neutrophils and monocytes to the site of injury. Early reperfusion therapy amplifies this inflammatory cell influx. Neutrophil release a variety of pro-inflammatory factors, including human neutrophil elastase (HNE). HNE has a wide range of substrates. Preclinical studies have demonstrated that neutrophil depletion or inhibition of neutrophil elastase attenuates post-ischemic inflammatory reperfusion injury within the myocardium. Recruitment of monocytes into the infarcted myocardium is followed by maturation and differentiation into macrophages. Macrophages play a key role in orchestrating inflammation and repair. Therapeutic manipulation of this healing process will only come from understanding mechanisms and targeting reparative pathways. “Ultrasmall superparamagnetic iron oxide particles” (USPIOs) extravasate through capillaries and are phagocytosed by tissue inflammatory cells. These cells are predominately macrophages, but neutrophils have also been shown to take up USPIOs. USPIO-enhanced MRI can identify areas of inflammation in models inflammation in various tissues. Therefore we hypothesised that USPIO enhanced MRI could identify and assess cellular inflammation of the myocardium. During coronary artery bypass graft surgery (CABG), the myocardium receives an immediate ischaemic insult that is exacerbated by post-ischaemic reperfusion inflammatory responses leading to increased myocardial injury. CABG surgery can therefore be used as a clinical model of myocardial infarction and inflammation. We investigated this with blood markers of inflammation, MRI scanning and USPIO. Elafin inhibits the destructive and inflammatory HNE enzyme. Beyond this elafin inhibits inflammatory cytokines and modulates the innate and adaptive immune systems. In preclinical studies elafin treatment is associated with reduced myocardial injury. As such, elafin has a marked potential for the treatment of cardiovascular disease involving inflammation. Therefore, we hypothesised that elafin will reduce perioperative ischaemic myocardial injury and inflammation in patients undergoing elective coronary artery bypass graft surgery. We demonstrated for the first time that USPIOs are taken up by the infarct tissue in patients with recent myocardial infarction and by the peri-infarct myocardium to a lesser degree. This represents a novel non-invasive method to further study cardiac inflammation and therapeutic interventions. All patients undergoing CABG surgery demonstrated >10-fold elevation above the 99th centile of cardiac troponin by high sensitivity assay (hs-cTnI) indicating the current universal definition of type 5 myocardial infarction lacks specificity. A peak hs-cTnI at 6 hours following CABG surgery appears to be related to the surgical process and non-specific myocardial injury whilst a continuing increase at 24 hours suggests myocardial infarction. We would suggest hs-cTnI sampling at 6 and 24 hours post CABG surgery together with ECG assessment for the routine detection and diagnosis of type 5 MI. Differing levels of humoral makers inflammation post CABG surgery occurred, and did not correlate directly with the length of cardiopulmonary bypass time or hs-cTnI release. For the first time we identified differing levels of inflammatory cell infiltrate into the myocardium post CABG. This varied from none to levels similar to infarcted myocardial tissues. Elafin did not attenuate myocardial ischemia-reperfusion injury and inflammation. Post-hoc analysis identified reduced cTnI concentrations at 6 hours in Elafin treated patients and it is possible that a bigger dose would have conferred protection out to 48 hours. Elafin did not attenuate the cellular infiltration into the myocardium post CABG surgery, but did appear to reduce inflammation in renal tissue. USPIO enhanced CMR holds major promise in the non-invasive assessment of myocardial inflammation post surgery.

Unlike other regenerative organs such as the liver, the adult mammalian heart does not regenerate tissue lost following injury such as myocardial infarction (MI). Instead a non-contractile fibrous scar develops that in the longer term leads to the development of heart failure (HF). In contrast to the adult, neonatal mammals, including mice and man, retain potent cardiac regenerative capacities and can replace myocardium lost following injury. Understanding the mechanisms underlying scar free repair in the neonate may help in development of new approaches to reduce the impact of myocardial injury in adults. In this thesis MI was induced by coronary artery ligation in mice at post-natal day 1 (P1). Novel electrocardiogram gated high resolution cardiac ultrasound was developed to permit non-invasive confirmation of injury 1 day later and regeneration 21 days later by loss, then restoration, of contractile function. Macrophages (MФ) play important roles in organ growth and homeostasis, and are required for scar-free regeneration of the neonatal mouse heart following MI. WNTs are secreted lipophilic proteins with multiple roles in development. MФ-derived WNTs are essential for scar free tissue regeneration following injury in the kidney, liver, and gut, but their role in the heart is unknown. The primary aim of this thesis was to investigate the role of MФ, and in particular MФ-derived WNTs in determining normal growth of the myocardium from neonate to adult and also in regeneration of the neonatal heart following injury. In wild-type neonatal mouse hearts, Csf1r-expressing cells density (mostly macrophages) was consistent across all time points studied. Three populations of resident cardiac mononuclear phagocytes were identified by flow cytometry: F4/80hi, CD11blo, Ly6C-ve - F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve. F4/80hi, CD11blo, Ly6C-ve cells were hypothesised to correspond to yolk-sac derived mononuclear phagocytes and F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve to foetal liver/bone marrow derived mononuclear phagocytes. Three phases of myocardial growth were identified by ultrasound and histological techniques: hyperplastic (P2-P8, with increased Ki67 and cardiac troponin immunopositive cells), hypertrophic/reorganisation (P8-P21, with increasing cardiomyocyte size and no change in left ventricle wall thickness), and finally hypertrophic solely (P21-P42, with increasing cardiomyocyte size and left ventricle wall thickness). Average coronary vessel size was shown to decrease between P2 and P8 whilst vessel density was increased. The number of α-smooth muscle actin (αSMA) coated vessels greatly increased between P8 and P42, indicating vessel maturation. Throughout all phases cardiac systolic function was maintained at steady state. Diastolic function was however shown to mature from a foetal to an adult pattern between P2 and P8, with reversal of the E:A wave ratio on Doppler ultrasound. In mice globally deficient in MФ due to a germline knock-out of the Csf1r gene (Csf1rnull mice), both body and heart weights were decreased from P7 onwards. The number of proliferating (Ki67+ve) cardiomyocytes at P1 and P7 was unchanged in Csf1r-null mice but there was a trend towards decreased cardiomyocyte size at P7, suggesting an influence on hypertrophic rather than hyperplastic growth of the myocardium. There was also a trend for slowed vascular network maturation, with a delay in the shift from large to smaller vessels in hearts from Csf1r-null mice. In mice with MФ-directed (Csf1r-icre mediated) depletion of Porcupine (Porcn), a gene encoding an enzyme required for WNT acylation and secretion cardiac growth, vascularisation, fibrosis and function were all similar in Cre-ve and Cre+ve animals until P41, when cardiomyocyte size and cardiac systolic function were both significantly increased in Cre+ve animals. However, the underlying mechanism is unknown. In the neonatal mice, Csf1r expressing cells, mostly MФ, were identified in association with regenerating myocardium after induction of MI at P1. Flow cytometry data showed that by P7 the putative resident yolk-sac derived population had mostly disappeared from the heart and was replaced by F4/80lo cells, similar to the pattern reported in the adult. In the regenerating myocardium, Axin2 expression was increased consistent with activation of canonical Wnt signalling. Expression of Wnt5b and Fzd2 receptor, both associated with fibrosis, was significantly increased relative to age matched uninjured hearts. MФ-directed depletion of Porcn did not influence either the functional decrease at day 1 or recovery at day 21 following induction of MI at P1. Coronary re-vascularisation was also unaffected by the genotype. However, retention of intra-myocardial fibrosis (picrosirius red staining) was significantly increased in hearts at day 21 post-MI from mice with MФ-directed depletion of Porcn. MФ-derived WNTs are therefore required for scar-free wound healing in the heart, as they are in the liver and the kidney where they regulate matrix metalloproteinase activity. In summary, novel ECG-gated high-resolution in vivo ultrasound developed in this project has allowed characterisation of cardiac structure and function during early post-natal growth and following injury and regeneration in neonatal mice. The resident MФ population of the heart is established pre-natally, and may play a role in determining maturation of the developing vascular network, although this does not involve MФ-derived Wnt signalling. Following MI, the MФ population may expand from bone marrow cells and MФ accumulate around the regenerating tissue. MФ derived WNTs are not required for regeneration of the neonatal myocardium but do have a role in ensuring scar free wound healing and this merits further investigation.

Background. The Cysteine-rich protein, Connective tissue growth factor, and Nephroblastoma overexpressed protein (CCN) family of matricellular proteins are signaling molecules found in the extracellular space, which can have pro-angiogenic, anti-inflammatory and anti-fibrotic properties. Their expression and role in repair and remodeling after myocardial infarction (MI) remains to be better elucidated. In this study, the age-associated expression of Nov (CCN3) and Wisp1 (CCN4) were examined post-MI in mice. Methods and Results. In vivo, MI was induced in young (6 week) and old (12-14 months) mice. Cardiac function was assessed by echocardiography, showing that LVEF was reduced in old mice (33.9%) at 14 days post-MI compared to young mice (43.9%; p=0.002). RT-qPCR analysis of harvested myocardial tissue revealed that mRNA expression of several matricellular proteins in healthy tissue was decreased by 2.5- to 5-fold in old compared to young mice (p=0.03 for Nov, p=0.04 for Wisp1, p=0.0002 for TnC, p=0.04 for TSP-1). Post-MI, mRNA expression of Nov was reduced in the infarct (by up to 13-fold; p<0.03) and border zone (by up to 16-fold; p<0.002) in old compared to young mice. Nov and Wisp1 protein expression was also reduced in old compared to young mice in the infarct and border zones; specifically, for Nov in the infarct zone (p=0.01) and the border zone (p=0.009) at 2 days post-MI and for Wisp1 in the infarct zone at 2 days (p=0.0003) and 14 days (p=0.003), along with 7 days post-MI in the border zone (p=0.0003). To identify possible sources of matricellular proteins, in vitro culture experiments were performed. The expression of Nov protein was increased (1.9-fold; p=0.006) in TGF-B stimulated cardiac fibroblasts after 48h, as was the expression of the myofibroblast marker a-SMA (1.7-fold; p=0.035). Wisp1 mRNA expression was increased (4.5-fold; p=0.03) in stimulated cardiac fibroblasts after 48h in a hypoxic environment. There was also a trend for increased mRNA expression of Nov (p=0.118) and Wisp1 (p=0.121) in M2 macrophages. Cardiac fibroblasts treated with Nov+TGF-B exhibited greater proliferation (by 29%; p0.01), as did those treated with Wisp1+TGF-B (by 16%; p<0.05). Treatment with Nov or Wisp1 led to an increase in viability of cardiac fibroblasts both in the presence (Nov; p=0.0004, Wisp1; p=0.01) and absence of TGF-B (Nov; p=0.0005, Wisp1; p=0.003). Summary. There is an age-associated difference in the expression of matricellular proteins Nov and Wisp1 between both healthy and MI mice. In vitro studies suggest that cardiac fibroblasts may produce Nov and Wisp1 upon their activation to myofibroblasts. The presence of these proteins was also shown to increase the proliferation and viability of fibroblasts. Therefore, reduced levels of Nov and Wisp1 in old mice may negatively affect the repair and remodeling process post-MI compared to young mice. A better understanding of Nov and Wisp1 function in aging and post-MI repair may help identify novel therapeutic targets for limiting damage post-MI and improving repair and heart function.

The phytocannabinoid cannabidiol (CBD) has a complex pharmacology which is thought to include, but is not limited to, an ability to act as an inverse agonist at the CB1 and CB2 receptors and an antagonist of GPR55. Moreover, is has been shown to reduce infarct size and ameliorate reductions in left ventricular function in vivo. These improvements in the pathogenesis of experimental MI are accompanied by a reduction in inflammatory cell migration to the area at risk. More recently it has been shown that CBD is anti-arrhythmic in acute experimental MI. Thus, it was suggested that the cardioprotective effects of CBD might be due to an anti-inflammatory action. In addition, GPR55 receptor activation is acknowledged to mediate mobilisation of intracellular Ca2+ (Ca2+i) which could potentially be pro-arrhythmic and so CBD, as an antagonist may confer cardioprotection via GPR55. However, the receptors and/or mechanisms responsible for mediating the cardioprotective effects of CBD are get to be determined. The present studies were therefore performed to; (1) better understand the pharmacology of CBD by assessing haemodynamic responses to CBD and other cannabinoids ligands in anaesthetised rats, (2) investigate the receptors involved in the anti-arrhythmic effect of CBD in a rat model of coronary artery occlusion (CAO), and (3) investigate if CBD can alter [Ca2+]i in isolated rat cardiomyocytes. The characterisation of the pharmacology of CBD in vivo showed that; firstly, CB1 receptor activation causes a hypotensive response which can be dose-dependently inhibited by AM251; secondly, both CBD and AM251 alone (a CB1 receptor antagonist and GPR55 agonist) can induce vasodepressor responses and finally, CBD can potentiate the AM251-mediated hypotension when co-administered, suggesting possible cross-talk between the CB1 and GPR55. Results from CAO studies showed that CBD and AM251 each have the capacity to reduce arrhythmias. Moreover, when CBD and AM251 were co-administered the anti-arrhythmic capacity of either alone was potentiated. However, the degree of potentiation was dependent on the order of administration, suggesting that more than one receptor is involved in the summative anti-arrhythmic effects. The investigation of cardiomyocyte [Ca2+]i suggested that AM251 can modulate [Ca2+]i at the level of the cardiomyocyte, while CBD cannot. These data give novel insight into the anti-arrhythmic effects of CBD and, moreover, for the first time demonstrate that AM251 is anti-arrhythmic. In addition, these data suggest a role for GPR55 in increasing [Ca2+]i via AM251.

Made available in DSpace on 2015-12-10T14:23:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-25. Added 1 bitstream(s) on 2015-12-10T14:29:24Z : No. of bitstreams: 1 000847329.pdf: 664528 bytes, checksum: 04c0638187c3d985069ffb5611009105 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: A insuficiência cardíaca é uma frequente complicação após o infarto agudo do miocárido (IAM), sendo que a remodelação cardíaca apresenta papel de destaque nesse cenário. O aumento do estresse oxidativo e do processo inflamatório estão associados com a remodelação cardíaca após o IAM. Devido ao grande impacto sócio econômico e às altas taxas de mortalidade, torna-se relevante a identificação de outros fatores que modulem o processo de remodelação cardíaca e podemos destacar a suplementação de alimentos com propriedades antioxidantes, como o tomate (Lycopersicon esculentum), e um de seus principais constituintes, o licopeno. Objetivo: Avaliar a influência da suplementação de tomate e licopeno na remodelação cardíaca após o IAM. Materiais e métodos: Ratos Wistar machos, com peso entre 200 e 250g, foram submetidos ao infarto experimental ou à cirurgia simulada e alocados em seis grupos: 1) grupo Sham (animais submetidos à cirurgia simulada) alimentado com dieta padrão (grupo- SC); 2) grupo Sham alimentado com dieta suplementada com licopeno 1mg/kg peso corporal/dia (grupo-SL); 3) grupo Sham alimentado com dieta suplementada com tomate (grupo-ST); 4) grupo infartado (animais submetidos ao infarto experimental) alimentado com dieta padrão (grupo-IC); 5) grupo infartado alimentado com dieta suplementada com licopeno 1mg/kg de peso corporal/dia (grupo-IL); 6) grupo infartado alimentado com dieta suplementada com tomate (grupo-IT). O licopeno e o tomate das dietas foram diluídos em óleo de milho para serem adicionados à ração (0,5ml de óleo/kg de peso corporal/dia) e os grupos controles tiveram a mesma quantidade de óleo adicionado. Após três meses de observação os animais foram submetidos ao estudo funcional, morfométrico, e bioquímico. Os valores obtidos foram apresentados em média ± desvio padrão. As variáveis que não preencheram os critérios de normalidade e de... / Introduction: Heart failure is a common complication after the acute myocardial infaction (AMI), and cardiac remodeling has a prominent role in this scenario. Increased oxidative stress and inflammation are associated with cardiac remodeling after AMI. Due to the great economic and social and high mortality rates, it's important to identify other factors that modulate the process of cardiac remodeling and among this factors are the supplementation of foods with antioxidant properties, such as tomato (Lycopersicon esculentum), and of its primary constituents, the lycopene. Objectives: Evaluate the influence of tomato and lycopene supplementation in cardiac remodeling after AMI. Methods: Male Wistar rats, weighing between 200 and 250g, were submitted to the experimental infarction or sham surgery and divided into six groups: 1) Sham group (animals undergoing sham surgery) fed a standard diet (SC group); 2) Sham group fed diet supplemented with 1 mg lycopene/kg body/day (SL group); 3) Sham group fed diet supplemented with tomato (ST group); 4) infarcted group (animals submitted to experimental infarction) fed a standard diet (IC group); 5) infarcted group fed diet supplemented with 1 mg lycopene/kg of body weight/day (IL group); 6) infarcted group fed diet supplemented with tomato (IT group). The lycopene and the tomato were dilute in corn oil to be add into the diet (0.5 ml of corn oil/kg body weight/day) and the standard group received the same oil. After three months of observation the animals underwent functional, morphometric and biochemical analysis. The values were expressed as mean ± standard deviation. The variables that did not meet the criteria of normality and equal variance were normalized before analysis. Comparisons between groups were made by two-way analysis of variance (ANOVA). For non-normalized data, we used Kruskal-Wallis test (comparison between the Sham groups, SC, SL and ... / FAPESP: 2012/17414-0

Orientador: Jean Leandro dos Santos / Banca: Leoberto Costa Tavares / Banca: Cíntia Duarte de Freitas Milagre / Resumo: Doenças cardiovasculares como infarto do miocárdio e acidente vascular encefálico ainda representam a principal causa de morte no Brasil. A aterosclerose é uma doença progressiva e silenciosa classificada como fator de risco para o desenvolvimento de doenças cardiovasculares. É caracterizada pelo aumento dos níveis de colesterol no plasma os quais são oxidados por radicais livres originando a lipoproteína de baixa densidade oxidada (LDLox). A fagocitose de LDLox por macrófagos permite a transformação destes em células espumosas, que são depositadas na camada íntima dos vasos. Após o rompimento do endotélio há o extravasamento do conteúdo da placa aterosclerótica para a circulação levando à formação de trombo. Este interrompe o fluxo sanguíneo em artérias e vasos, levando ao desenvolvimento de doenças cardiovasculares como infarto do miocárdio e acidente vascular encefálico. A terapia preventiva contra eventos aterotrombóticos é realizada com fármacos antiagregantes plaquetários. O ácido acetilsalicílico (AAS) é um dos fármacos mais utilizados na prevenção de aterotrombose, mas apresenta limitações como indução de ulcerações gástricas e bloqueio de somente uma via de agregação plaquetária. Neste sentido, e em continuidade com a linha de pesquisa visando à busca de novos fármacos antiagregantes plaquetários obtidos por estratégia de modificação molecular implantados no Laboratório de Pesquisa e Desenvolvimento de Fármacos (Lapdesf - UNESP Araraquara), realizou-se a hibridação molecular das subunidades presentes no AAS e furoxanos sendo ambas partes espaçadas pela subunidade N-acilhidrazona. O furoxano é conhecido por suas propriedades doadoras de óxido nítrico (NO) responsável pelo efeito antiagregante plaquetário. Assim, o objetivo deste trabalho é a síntese de novos compostos derivados do AAS, mais potentes e seguros para serem usados como antiagregantes plaquetários. Os ... / Abstract: Cardiovascular diseases such as myocardial infarction and stroke still represents the leading cause of death in Brazil. Atherosclerosis is a silent progressive disease classified as a risk factor for developing cardiovascular diseases. It is characterized by increased levels of plasma cholesterol which are oxidized by free radicals resulting in oxidized low density lipoprotein (oxLDL). The oxLDL phagocytosis by macrophages allows for transformation into foam cells, which are deposited in the intima of vessels. After the disruption of the endothelium occurs the leak plaque's contents into the circulation driving to thrombus formation. This blocks the blood flow in arteries and vessels, leading to the development of cardiovascular diseases such as myocardial infarction and stroke. The preventive therapy against atherothrombotic events is performed with antiplatelet drugs. Acetylsalicylic acid (ASA) is a drug commonly used to prevent atherothrombosis, but it has limitations such as induction of gastric ulcer and blocking only one route of platelet aggregation. Continuing goals finding new antiplatelet drugs obtained by molecular modification strategy implemented in the Laboratory of Drug Research and Development (Lapdesf - UNESP Araraquara), held the molecular hybridization of subunits present in AAS and furoxans being spaced by subunit N-acylhydrazone. The furoxano is known for its donor properties of nitric oxide (NO) responsible for the antiplatelet effect. The objective of this work is the synthesis of new compounds derived from AAS, most powerful and safe to use as antiplatelet agents. Compounds were synthesized using divergent route for obtaining derivatives furoxans, N-acilhidrazones spacers and the hybrid compounds. All compounds were purified and characterized by analytical methods such as, Infrared Absorption Spectroscopy, Mass Spectrometry and Nuclear Magnetic Resonance. N-acilhidrazones spacers was possible to perform the ... / Mestre

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