Indiana University Purdue University Indianapolis / H2S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear if H2S works through nitric oxide-dependent pathways in the intestine. We appreciated that H2S was able to improve post-ischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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Submitted by Gizele Lima (gizele.lima@inpa.gov.br) on 2017-09-04T14:37:17Z No. of bitstreams: 2 jean_dissertação.pdf: 19953772 bytes, checksum: 15f3b6dce2eb8609d2e5f4ec2b7cc8b7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-09-04T14:37:17Z (GMT). No. of bitstreams: 2 jean_dissertação.pdf: 19953772 bytes, checksum: 15f3b6dce2eb8609d2e5f4ec2b7cc8b7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-06-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This study aims to investigate the decadal variability of the occurrence of ENSO events, classified as El Niño/La Niña central (EN-CP/LN-CP), east (EN-EP/LN-EP) and without differentiating the types (Total) and its relationship with precipitation over South America, using observational analyzes for the period 1901 to 2013. The Monthly time series of Sea Surface Temperature (SST), Average Sea Level Pressure (SLP), velocity potential (χ) at 200 hPa and precipitation. Were used initially ENSO events were selected, and occurrence rates of the different types of ENSO were constructed within 5 and 10 year moving windows. Wavelet analyzes these indices show significant scales with peaks ranging from 12 to 22 years. Furthermore, the results show that the decadal variability of ENSO occurrence rates is related to low frequency oscillations such as the Pacific Decadal Oscillation (PDO) and the Atlantic Multidecadal Oscillation (AMO). The occurrence rates of EN-Total and EN-CP events show significant positive correlations with the PDO index, while the indexes of EN-EP events are marginally associated with AMO. For La Niña events, significant positive (negative) correlations between occurrence indexes and PDO (AMO) indexes are found for the cases of LN-Total and LN-EP. Associated with the decadal patterns of SST anomalies, decadal changes in atmospheric circulation are noted, mainly in relation to Walker circulation. These changes in the atmospheric circulation influence the precipitation pattern on South America during the El Niño events, causing significant negative anomalies in the precipitation over the central part between the latitudes of 5°N - 10°S. In relation to La Nina events, Walker circulation is most intense in the central and western Pacific and regions of Indonesia and the eastern Indian Ocean. Significant positive variations in precipitation over South America are restricted to northern Brazil, including the states of Pará and Amapá. On the other hand, negative precipitation variations in the central-eastern part of Brazil may be associated with variations of the SLP over the Southern Tropical Atlantic. These results show the importance of low-frequency oscillations in ENSO variability and may be useful for monitoring purposes. / Este estudo tem por objetivo investigar a variabilidade decenal da ocorrência de eventos ENOS, classificados em El Niño/La Niña central (EN-CP/LN-CP), leste (EN-EP/LN-EP) e sem diferenciar os tipos (Total) e sua relação com a precipitação sobre a América do Sul, utilizando análises observacionais para o período de 1901 a 2013. Foram utilizadas as séries mensais da Temperatura da Superfície do Mar (TSM), Pressão ao Nível Médio do Mar (PNM), potencial de velocidade (χ) em 200 hPa e precipitação. Inicialmente os eventos ENOS foram selecionados, e índices de ocorrência dos diferentes tipos de ENOS foram construídos dentro de janelas móveis de 5 e 10 anos. Análises de ondeletas desses índices mostram escalas significativas com picos variando de 12 a 22 anos. Ainda, os resultados mostram que a variabilidade decenal dos índices de ocorrência do ENOS está relacionada com as oscilações de baixa frequência como a Oscilação Decenal do Pacífico (PDO) e a Oscilação Multidecenal do Atlântico (AMO). Os índices de ocorrências dos eventos EN-Total e EN-CP apresentam correlações positivas significativas com o índice da PDO, enquanto que os índices dos eventos EN-EP são marginalmente associados a AMO. Para os eventos La Niña, há correlações positivas (negativas) significativas entre os índices de ocorrência e os índices da PDO (AMO) para os casos de LN-Total e LN-EP. Associadas aos padrões decenais de anomalias de TSM, mudanças decenais na circulação atmosférica são notadas, principalmente em relação à circulação de Walker. Essas mudanças na circulação atmosférica influenciam o padrão de precipitação sobre a América do Sul durante os eventos de El Niño, causando anomalias negativas significativas na precipitação sobre a parte central entre as latitudes de 5°N – 10°S. Em relação aos eventos de La Nina, as variações na circulação de Walker são mais intensas sobre o Pacífico central e oeste e regiões da Indonésia e leste do Oceano Índico. As variações positivas significativas na precipitação sobre a América do Sul se restringem à região norte do Brasil, incluindo os estados do Pará e Amapá. Por outro lado, variações negativas de precipitação na parte centro-leste do Brasil, podem estar associadas às variações da PNM sobre o Atlântico Tropical Sul. Esses resultados mostram a importância das oscilações de baixa frequência na variabilidade do ENOS e podem ser úteis para propósitos de monitoramento climático.

This study examines the possibility of the use of low frequency sound in the stimulation of Endothelial Nitric Oxide Synthase (eNOS), an enzyme which regulates the synthesis of NO from the amino acid L-arginine. To test this hypothesis, oximetry was used to measure changes in hemoglobin saturation in a subject exposed to a 45Hz signal, and accelerometers were used to monitor attenuation of two source frequencies (45Hz and 8Hz) across 5 subjects at varying source transducer locations. The data from the oximetry monitoring was only suggestive, but its interpretation is encouraging for future avenues of study. Examining the attenuation of the applied frequencies showed, as expected, did not show a strong dependence on the height or weight of the subject, with little transmission loss throughout the body. These data establish the firm groundwork for future experimentation to reduce the methodology into a clinically feasible medical device

This study examined the DNA methylation profile of endothelial nitric oxide synthase (eNOS) in the placental villous trophoblast in first, second trimester and healthy term placentas. Syncytiotrophoblast DNA revealed a heterogeneous methylation pattern in the first trimester eNOS proximal promoter and transitioned to a densely methylated pattern at term. Healthy, term syncytiotrophoblast and cytotrophoblast obtained through cytotrophoblast isolation technique provided purified cell samples for RNA and DNA extraction. Real-time PCR (rt-PCR) verified the presence and quantity of eNOS mRNA. In summary, the main findings of this thesis are heterogeneous methylation in first trimester compared to hypermethylation at term; greater eNOS expression and variable methylation in term syncytiotrophoblast compared to cytotrophoblast. A heterogeneous methylation pattern in eNOS has been identified in this study and recent stem cell studies in our lab, and we propose it represents plasticity in gene expression, particularly in early development.

This study examined the DNA methylation profile of endothelial nitric oxide synthase (eNOS) in the placental villous trophoblast in first, second trimester and healthy term placentas. Syncytiotrophoblast DNA revealed a heterogeneous methylation pattern in the first trimester eNOS proximal promoter and transitioned to a densely methylated pattern at term. Healthy, term syncytiotrophoblast and cytotrophoblast obtained through cytotrophoblast isolation technique provided purified cell samples for RNA and DNA extraction. Real-time PCR (rt-PCR) verified the presence and quantity of eNOS mRNA. In summary, the main findings of this thesis are heterogeneous methylation in first trimester compared to hypermethylation at term; greater eNOS expression and variable methylation in term syncytiotrophoblast compared to cytotrophoblast. A heterogeneous methylation pattern in eNOS has been identified in this study and recent stem cell studies in our lab, and we propose it represents plasticity in gene expression, particularly in early development.

The dissection of etiology of hypertension is a medical imperative. In the central nervous system, rostral ventral lateral medulla (RVLM) plays an essential role in the maintenance of arterial pressure and heart rate through tonic activation of the sympathetic vasomotor activity and regulation of baroreflex response. Oxidative stress of an enhanced cellular content of the reactive oxygen species, in particular the superoxide anion (O2-), has been implicated in hypertension. Superoxide dismutase (SOD) is one of the most important defense enzymes against the oxidative stress through catalysis of O2- into O2 and H2O2. SOD treatment has been demonstrated to decrease arterial pressure. Moreover, in addition to its peripheral vasodilatory effect, nitric oxide (NO) plays an active role in central regulation of arterial pressure and heart rate via modulation of the autonomic system. In the RVLM, both O2- and NO have been demonstrated to be involved in hypertension. Interactions between these two molecules, however, are not understood. The aims of this study are therefore to establish the significance of O2- and NO in the RVLM on blood pressure regulation in hypertension and to examine whether O2- interacts with NO to participate in the pathogenesis of hypertension. To examine their long term effects on mean systemic arterial pressure (MSAP) and heart rate (HR), SOD and/or NO was over-expressed by microinjection of the adenoviral vectors encoding the endothelial NO synthase (AdeNOS) and/or mitochondrial SOD (AdSOD2) into RVLM of the normotensive Wistar-Kyoto (WKY) rats or the spontaneously hypertensive rats (SHR). I found that microinjection of AdeNOS in the RVLM of SHR or WKY rats significantly decreased MSAP or HR that lasted for around 10 days postinjection. The hypotensive effect of AdeNOS was significantly greater in SHR than WKY rats. The AdeNOS-promoted hypotension in SHR, but not WKY rats, was followed by a rebound hypertension, detected in 28 days after the gene transfer. In the AdeSOD2-treated animals, I found a significant decrease in the MSAP in SHR, but not WKY rats, that lasted for about 7 days postinjection. On the other hand, no change in HR was detected in either SHR or WKY rats after the AdSOD2 gene transfer into the RVLM. In animals that received co-microinjection into the bilateral RVLM of AdeNOS and AdSOD2, there was a further prolonged decrease in MSAP or HR in SHR. The rebound hypertension observed in the AdeNOS-treated SHR was reversed to hypotension in the AdeNOS+AdSOD2-treated SHR. There was no difference in the hypotensive or bradycardiac effects in WKY rats that received the AdeNOS+AdSOD2 or AdeNOS gene transfer. Together these results suggest that (1) NO in RVLM plays an important role in central regulation of arterial pressure and heart rate under both normotensive and hypertensive conditions. A greater reduction in MSAP in the AdeNOS-treated SHR further indicates a reduced action of NO at the RVLM in the pathogenesis of hypertension. (2) An excessive oxidative stress of a reduced function of SOD2 in RVLM may be an important factor in neural mechanism of hypertension in SHR. The same mechanism, at the same time, may underlie the rebound hypertensive observed in the AdeNOS-treated SHR. (3) The excessive oxidative stress in the RVLM contributes to hypertension by at least two mechanisms. One is to cause oxidative injury in the RVLM and the other is to interact with NO to decrease already insufficient activity of NO in central cardiovascular regulation.

Submitted by Milena Dias (milena.dias@ufpe.br) on 2015-03-12T17:58:26Z No. of bitstreams: 2 Dissertação Rafaella do Nascimento.pdf: 2590367 bytes, checksum: 6d3de6f0c3e697e651f90e0cf7a6d5e1 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-03-12T17:58:27Z (GMT). No. of bitstreams: 2 Dissertação Rafaella do Nascimento.pdf: 2590367 bytes, checksum: 6d3de6f0c3e697e651f90e0cf7a6d5e1 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2013 / A gestação é um fenômeno fisiológico que se inicia com a fecundação e progride no sentido de promover um ambiente adequado onde o feto possa crescer e formar um novo indivíduo com todo seu potencial genético expresso. Durante este período, os níveis lipídicos normalmente aumentam para permitir a manutenção da homeostase entre mãe e feto. Níveis lipídicos anormais estão relacionados com disfunção endotelial, reduzindo a produção de óxido nítrico (NO) e causando complicações para mãe e para o desenvolvimento fetal. O NO é principal regulador de eventos feto-placentários sendo produzido a partir da ação de 3 isoformas da óxido nítrico sintase (NOS). Polimorfismos de base única (SNPs) na NOS endotelial (eNOS) tem sido correlacionados à diversas patologias, sendo T-786C um dos SNPs responsáveis por reduzir a expressão da eNOS em 50%. Nosso estudo estabeleceu uma análise sobre estudo sobre o polimorfismo T-786C no gene da eNOS em mulheres no terceiro trimestre de gravidez, observando a possível associação com moléculas lipídicas e com a proteína c-reativa (PCR). Adicionalmente, a partir de ferramentas in silico, foram desenhados modelos de interação proteína-proteína (networks) para compreensão da importância do metabolismo da eNOS em condições normais e com patologias. Amostras de 92 mulheres grávidas foram submetidas à extração de DNA, identificação do polimorfismo T-786C por PCR-RFLP, e análise dos níveis de colesterol total (CT), HDL, LDL, triglicerídeos (TG) e PCR. Análise genotípica apresentou uma população de 71,73% TT, 26,08% CT e apenas 2,17% CC, estando o alelo C-786 presente em 15.21% do grupo estudado. Em relação à análise bioquímica, observou-se significância apenas para PCR quando as pacientes foram agrupadas por níveis sorológicos (normal ou alterado) de acordo com o genótipo da paciente. A CRP atua diretamente no desacoplamento da enzima eNOS prejudicando sua atividade e diminuindo a produção de NO, e servindo como marcador de eventos cardiovasculares. A partir das análises de bioinformática construímos duas networks. A primeira, denominada eNOSNet, possui 51 nós e 361 arestas de interação, mostrando proteínas ligantes da eNOS, pequenas moléculas e seus complexos formados. A segunda network, denominada eNOSNetD, relaciona proteínas envolvidas na via normal da eNOS com doenças descritas para o polimorfismo T-786C, tais como: doenças relacionadas ao sistema cardíaco, neurológico, à neoplasias e ao metabolismo lipídico, glicídico, protéico e hormonal. Estes dados podem ajudar na compreensão sobre a progressão de doenças que envolvem o funcionamento da eNOS e seus possíveis tratamentos e diagnósticos.

Increasing age is the single biggest independent risk factor for cardiovascular disease, which is in turn the leading cause of morbidity and mortality worldwide. Ageing is associated with hypertension and metabolic changes which all increase the risk of the development of cardiovascular disease. In young, healthy individuals, perivascular adipose tissue (PVAT) secretes factors that can influence vascular contractility, exerting a net anti-contractile effect against numerous vasoconstrictors including the thromboxane A2 mimetic U46619 and α1-adrenoceptor phenylephrine. Whilst it is known that dysfunction in PVAT can contribute to obesity-related hypertension, little is known whether similar dysfunction occurs with ageing. In young Wistar rats, wire myography and pharmacological studies showed that the anti-contractile effect of PVAT in the presence of U46619 is dependent on both PVAT-derived nitric oxide and prostaglandins, whereas the anti-contractile effect in the presence of phenylephrine is nitric oxide independent. This finding was supported by Western blot experiments that showed increased phosphorylation of endothelial nitric oxide synthase (eNOS) in PVAT following U46619 incubation, but not phenylephrine. In the Wistar rat model of ageing used, wire myograph studies revealed that the PVAT anti-contractile effect in the presence of phenylephrine is preserved at 24 months of age, but in in the presence of U46619 is lost. Furthermore PVAT from aged animals had a deleterious effect on endothelial function, suggesting changes in its secreted factors. These changes are accompanied by alterations in the expression and activation of key enzymes in the nitric oxide synthesis pathway within the PVAT as measured by Western blot, as well as alterations in cardiometabolic phenotype including hypertension, hyperglycaemia and insulin resistance. Taken together these findings suggest that previously unidentified age-related PVAT dysfunction may contribute to age-related hypertension and thus may provide a potential therapeutic target for future study.