No description available.

Individuals with diabetes mellitus (DM) have a 2 to 4-fold increased risk of cardiovascular diseases (CVD) compared to those without DM. A contributing factor to the development of CVD is atherosclerosis, a chronic inflammatory disease causing plaque build-up in medium to larger arteries. Increasing evidence suggests that hypoxia within the arterial wall is known to promote atherosclerosis, however the underlying mechanisms remain unclear. Our lab has previously shown that hyperglycemic APOE-deficient mice have impaired angiogenesis of the aortic vasa vasorum, increased arterial hypoxia, elevated vascular inflammation and accelerated atherosclerosis development at 15 weeks of age compared to normoglycemic APOE-deficient controls. The objective of this study is to elucidate the mechanisms associated with these differences, specifically the reductions in vasa vasorum. The effects of hyperglycemia and specific interventions to modulate endoplasmic reticulum stress (4-phenylbutyric acid (4PBA)), oxidative stress (n-acetyl-cysteine (NAC)) and advanced glycation end products (pyridoxamine (PX)) are examined in vivo and in vitro. Results demonstrate that human cardiac microvascular endothelial cells (HMVEC-Cs) have reduced angiogenesis in high glucose compared to normal glucose conditions in both hypoxic and normoxic environments. This may be associated with reduced expression of vascular endothelial growth factor A (VEGF-A). Treatment with PX or NAC in hypoxic, high glucose conditions increased the angiogenesis and expression of VEGF-A in HMVEC-Cs. Pilot studies suggest that PX, NAC or 4PBA supplementation are well tolerated in drinking water using STZ mouse models. Future studies should assess the direct effects of each of the chemical interventions on vasa vasorum angiogenesis, arterial hypoxia and atherosclerosis. These results suggest that oxidative stress and advanced glycation end products play a more significant role in reducing microvessel angiogenesis in vitro. Understanding of the non-canonical pathways of atherosclerosis progression in the presence of DM will facilitate the development of novel and more specific treatments for this ongoing epidemic. / Thesis / Master of Science (MSc) / Individuals with diabetes have elevated blood glucose levels which can damage blood vessels throughout the body. This damage can result in the development of cardiovascular diseases. The vasa vasorum is a distinct microvessel network that surrounds the walls of large arteries. Damage to the vasa vasorum can result in decreased oxygen supply to the artery wall, triggering low oxygen environments and accelerated atherosclerosis development. In this study we aim to investigate the mechanisms associated with high glucose induced vasa vasorum damage. Results demonstrate reduced vessel formation of human endothelial cells in high glucose conditions. This decrease correlates with advanced glycation end products and oxidative stress inducing a decreased expression of vascular endothelial growth factor A, a known stimulator of vessel formation. Understanding of the unorthodox pathways of atherosclerosis in diabetes will facilitate the development of new and more effective treatment strategies for this ongoing epidemic.

Thesis (Ph. D.)--University of Virginia, 2009. / Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Les maladies cardio-vasculaires sont responsables de la vaste majorité des décès dans les pays industrialisés. La plupart de ces maladies sont dues à l'athérosclérose, processus manifesté par le développement de lésions (plaques d'athéromes) dans les parois vasculaires. La présence de ces plaques conduit à la réduction de la lumière du vaisseau et, par conséquent, à des complications graves, tel que l'infarctus du myocarde. Les patients ont pour issue la méthode d'angioplastie qui consiste à écraser la plaque athéromateuse à l'aide d'un ballonnet pour accroître la lumière du vaisseau obstrué. Toutefois, cette intervention entraîne une abrasion de l'endothélium et un étirement important des cellules musculaires lisses (CML) situées dans la profondeur de la paroi. Chez environ un tiers à la moitié des patients, la multiplication des CMLs conduit à une nouvelle réduction de la lumière artérielle. C'est la resténose. Les travaux de recherche ont permis le déploiement de plusieurs thérapies pharmacologiques et mécaniques mais les résultats tant anticipés suite aux études animales ne sont pas reproductibles chez l'humain pour la vaste majorité des tactiques. Notre équipe s'est intéressée au Système Rénine-Angiotensine (SRA) car son implication dans la resténose est non-négligeable. De plus, le succès des inhibiteurs de l'enzyme de conversion de l'angiotensine (iECA) chez l'animal a confirmé son rôle. Cependant, les essais cliniques ne sont guère convaincants et c'est ce qui a incité plusieurs à s'intéresser aux récepteurs de !'angiotensine II (Ang Il). Nos études antérieures avec le modèle de la carotide de rat ont révélé que les antagonistes non-peptidiques de l' Ang II sélectifs pour AT[indice inférieur 1] diminuaient partiellement la prolifération néointimale. Parallèlement, nous avions traité nos animaux avec un antagoniste peptidique non-sélectif pour réaliser que ce dernier en inhibait la presque totalité. Notre hypothèse de travail est que les antagonistes nonpeptidiques et les iECAs ont une efficacité limitée sur la réduction myointimale. Nous avons effectué une courbe dose-réponse avec un antagoniste non-peptidique sélectif pour AT[indice inférieur 1] et une seconde courbe avec un antagoniste non-peptidique mais sélectif pour les deux sous-types de récepteurs (AT[indice inférieur 1] et AT[indice inférieur 2]. De plus, nous avons traité nos animaux avec un iECA seul et combiné avec un antagoniste non-peptidique. Le bilan confirme l'efficacité limitée des antagonistes non-peptidiques de I' Ang II et établit que la coapplication de drogues ne suffit pas pour réduire la prolifération néointimale avec la même efficacité qu'observée avec l'antagoniste peptidique. Dans un deuxième temps, nous avons cherché à développer un nouveau modèle animal de la resténose afin de palier aux critiques dont font l'objet les modèles actuels et aussi permettre la validation de nos données antérieures. Nous suggérons que le furet pourrait devenir une bonne alternative aux modèles existants.

No description available.

No description available.

Calcifications in carotid atheromas can be detected in a panoramic radiograph (PR) of the jaws. A carotid artery calcification (CAC) can indicate presence of significant (≥ 50%) carotid stenosis (SCS). The aim of this thesis was to (1) determine the prevalence of SCS and burden of atherosclerotic disease among patients revealing CACs in PRs, (2) determine the prevalence of CACs in PRs among patients with SCS, (3) analyze whether the amount of calcium and/or (4) the radiographic appearance of the CACs, can improve the positive predictive value (PPV) for SCS detection among patients with CACs in PRs. The thesis is based on four cross-sectional studies. Two patient groups were prospectively and consecutively studied. Group A represented a general adult patient population in dentistry examined with PR presenting incidental findings of CACs. These patients were examined with carotid ultrasound for presence or absence of SCS and their medical background regarding atherosclerotic related diseases and risk factors was reviewed. An age and gender matched reference group was included for comparisons. Group B comprised patients with ultrasound verified SCS, examined with PR prior to carotid endarterectomy. The PRs were analysed regarding presence of CACs. The extirpated plaques were collected and examined with cone-beam computed tomography (CBCT) to determine the amount of calcium. The radiographic appearance of CACs in PRs from Group A and B were evaluated for possible association with presence of SCS. In Group A, 8/117 (7%) of patients with CAC in PRs revealed SCS in the ultrasound examination, all were found in men (8/64 (12%)). Patients with CACs in PRs revealed a higher burden of atherosclerotic disease compared to participants in the reference group (p <0.001). In Group B, where all patients had SCS, 84% revealed CACs in PRs and 99% of the extirpated plaques revealed calcification. CACs with volumes varying between 1 and 509 mm3 were detected in the PRs. The variation in volume did not correlate to degree of carotid stenosis. The radiographic appearance that was most frequently seen in neck sides with SCS (65%) was also frequently found in neck sides without SCS (47%) and therefore the PPV did not improve compared to the PPV solely based on presence of CACs. CACs in PRs are more associated with SCS in men than in a general population and patients with CACs in PRs have a higher burden of atherosclerotic disease. The majority of patients with SCS show CACs in PRs and the majority of extirpated carotid plaques reveal calcification. The volume of CAC and specified radiographic appearance does not increase the PPV for SCS in patients with CACs in PRs. In conclusion patients with CACs in PRs, and without previous record of cardiovascular disease, should be advised to seek medical attention for screening of cardiovascular risk factors. / Bakgrund Inom ramen för specialist- och allmäntandvård utförs panoramaröntgen-undersökningar dagligen på såväl barn som vuxna. En panoramaröntgenbild (PB) är en översiktsbild som är specifikt anpassad till att återge området för tänder och käkar. Utöver det, avbildas även delar av halsen och som bifynd ibland förkalkningar belägna i området för halspulsådern (karotiskärlet). Dessa förkalkningar kallas för karotisförkalkningar och är ett tecken på åderförkalkning. Åderförkalkning består i huvudsak av en fettrik plackansamling i kärlväggen. Placket kan med tiden förkalkas till varierande grad. Det är dessa förkalkningar vi kan se i PB. När en åderförkalkning ökar i volym kan den utgöra en förträngning i kärlet. Då förträngningen av kärldiametern är ≥ 50% benämns åderförkalkningar belägna i karotiskärlet för ”signifikanta karotisstenoser” (SKS). Graden av förträngning bedöms som regel med ultraljudsundersökning av halskärlen. Bitar av SKS kan lossna varvid det bildas små blodproppar. Eftersom halspulsådern försörjer främre hjärnhalvan med blod så kan dessa bitar täppa till ett av hjärnans blodförsörjande kärl och leda till stroke (slaganfall). För att minska risken att drabbas av stroke kan man ibland operera bort SKS (karotisplacket). Syfte Syftet med denna avhandling var att ta reda på (1) hur många av de patienter som blir undersökta med PB inom tandvården som uppvisar karotisförkalkningar, hur stor andel som har SKS samt utreda om patienter med förkalkningar i PB i större utsträckning är drabbade av hjärtkärlsjukdomar/risk faktorer, (2) hur ofta utopererade karotisplack innehåller kalk och hur ofta patienter med känd SKS uppvisar karotisförkalkningar i PB, (3) huruvida förkalkningsmängden i utopererade karotisplack är korrelerad till förträngningsgrad, och (4) huruvida det finns något specifikt radiografiskt utseende på karotisförkalkningar i PB som kan användas för att identifiera en större andel patienter med SKS bland patienter som uppvisar karotisförkalkningar i PB, det vill säga minska risken för att skicka patienter utan SKS på ultraljudsundersökning. Material och metoder Materialet bestod av två huvudgrupper av patienter. Grupp A bestod av patienter undersökta inom tandvården med PB som uppvisat karotisförkalkningar. Alla dessa patienter undersöktes med ultraljud för att bedöma förekomst av SKS. Den medicinska journalen granskades avseende tidigare förekomst av åderförkalkningsrelaterade sjukdomar och risk faktorer. En köns- och åldersmatchad kontrollgrupp utan karotisförkalkningar i PB analyserades på motsvarande sätt för jämförelse. Grupp B bestod av patienter med känd SKS som före operativt avlägsnande av karotisplack undersöktes med PB. PB granskades avseende förekomst av karotisförkalkning och utopererade karotisplack avseende kalkinnehåll. Förkalkningsmängden i de utopererade karotisplacken korrelerades dels till möjlighet att identifiera karotisförkalkning i PB samt till förträngningsgraden i kärlen. Karotisförkalkningarnas utseende delades in i grupper för att utvärdera om vissa utseenden i större utsträckning kunde associeras till förekomst av SKS. Resultat I Grupp A uppvisade 8/117 (7%) patienter SKS, alla var män, 8/64 (12%). Patienter med karotisförkalkningar i PB hade oftare åderförkalkningsrelaterade sjukdomar och risk faktorer (p < 0,001). I Grupp B hade 84% av patienterna med SKS karotisförkalkning i PB. Bland de utopererade karotisplacken innehöll 99% förkalkningar och förkalkningsvolymen varierade från 1-509 mm3. Möjligheten att upptäcka karotisförkalkning i PB var oberoende av om förkalkningsvolymen var stor eller liten. Förkalkningsvolymen var heller inte korrelerad till hur stor förträngning av kärlet en SKS (≥ 50%) orsakat. Ett radiografiskt utseende på karotisförkalkningar i PB noterades i 65% av de halssidor som hade en SKS. Detta specifika radiografiska utseende återfanns dock även i 47% av halssidor utan SKS. Andelen falskt positiva patienter var således fortsatt hög. Slutsats Vi fann att 12% män med karotisförkalkningar i PB, undersökta i en generell population inom tandvården, uppvisar SKS. Patienter med karotisförkalkningar i PB uppvisar fler riskfaktorer och är oftare drabbade av hjärt-kärlsjukdomar än patienter utan karotisförkalkningar i PB. Majoriteten av patienter med SKS uppvisar karotisförkalkningar i PB och nära 100% av utopererade karotisplack innehåller kalk. Förkalkningsmängden påverkar inte möjligheten att upptäcka karotisförkalkning i PB. Förkalkningsmängd och specificerade radiografiska utseenden hos karotisförkalkningar i PB förutsäger inte SKS bättre än definitionen ”förkalkning ja eller nej”. Dessa parametrar kan således inte användas till att förfina urvalet bland patienter som uppvisar karotisförkalkning i PB mot högre andel patienter med SKS. Individer med karotisförkalkningar i PB bör uppmanas konsultera vården för undersökning av eventuella risk faktorer för hjärt-kärlsjukdom.

Atherosclerosis is thought to be initiated by endothelial cell dysfunction. Research described in this dissertation is focused on interactions of nutrients, cytokines and pharmaceutical compounds in the intracellular signaling pathways leading to endothelial cell activation. The flavonoid quercetin could significantly downregulate the inflammatory pathways induced by linoleic acid as determined by DNA binding assays of the proinflammatory transcription factors nuclear factor-kappaB and activator protein-1 as well as by gene expression studies of interleukin-6 and vascular adhesion molecule-1. Interestingly, quercetin and vitamin E also prevented the linoleic acid-induced activation of PPAR DNA binding - suggesting a role of oxidation in the fatty acid-mediated induction of PPAR. In addition, we studied an interaction of zinc with the antiinflammatory transcription factors, peroxisome proliferator activated receptors (PPARs) alpha and gamma. Our data suggest that PPAR alpha and gamma and their synthetic agonists require zinc for their antiinflammatory properties in endothelial cells. We could confirm the importance of zinc in PPAR gamma signaling in vivo by a decreased PPAR DNA binding activity in livers of zinc deficient mice. Furthermore, zinc had dramatic lipid lowering effects in LDL-receptor deficient mice on a diet rich in corn oil. Triglycerides, phospholipids and cholesterol levels were significantly elevated in mice receiving a zinc deficient diet when compared to control and where decreased in zinc supplemented animals. Zinc deficiency also increased oxidative stress as determined by quantitation of plasma isoprostanes and mRNA expression of glutathione reductase. In conclusion, our data show novel interactions of proinflammatory nutrients, such as linoleic acid, with antioxidant and anti-inflammatory nutrients, such as quercetin and zinc.

Endothelial activation is considered to be an early and critical event in the pathology of atherogenesis which can be modified by environmental factors such as diet, pollutants, and lifestyle habits. Dietary andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids have been reported to either amplify or diminish inflammatory responses related to atherosclerosis development. However, the interactions of andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids with inflammatory cytokines or organic pollutants on endothelial cell activation are not well understood. The studies presented in this dissertation tested the hypothesis that andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids alone, or in varying ratios can differently modulate pro-atherogenic mediators and inflammatory responses that are initiated by tumor necrosis factor- andamp;aacute; (TNF-andamp;aacute;) or polychlorinated biphenyls (PCBs) in endothelial cells. Exposure to TNF-andamp;aacute; induced oxidative stress, p38 MAPK, NF-andamp;ecirc;B, COX-2 and PGE2, which was amplified by pre-enrichment with linoleic acid but blocked or reduced by andamp;aacute;-linolenic acid. Furthermore, TNF-andamp;aacute;-induced caveolin-1 up-regulation and the co-localization of TNF receptor-1 with caveolin-1 was markedly increased in the presence of linoleic acid and diminished by andamp;aacute;-linolenic acid. Silencing of the caveolin-1 gene completely blocked TNF-andamp;aacute;-induced production of COX-2 and PGE2 and significantly reduced the amplified response of linoleic acid plus TNF-andamp;aacute;. These data suggest that omega-6 and omega-3 fatty acids can differentially modulate TNF-andamp;aacute;-induced inflammatory stimuli and that caveolae and its fatty acid composition play a regulatory role in these observed metabolic events. Besides cytokines, lipophilic environmental contaminants such as PCBs can also trigger inflammatory events in endothelial cells. Our data suggest that increasing the relative amount of andamp;aacute;-linolenic acid to linoleic acid can markedly decrease oxidative stress and NF-andamp;ecirc;B-responsive genes. The inhibitor study revealed that the modulation effect of andamp;ugrave;-6 and andamp;ugrave;-3 fatty acids on PCB toxicity was mainly through the oxidative stress sensitive transcription factor, NF-andamp;ecirc;B. In conclusion, our studies demonstrate that different dietary fats can selectively modulate vascular cytotoxicity caused by TNF-andamp;aacute; as well as by persistent organic pollutants such as PCBs. We also demonstrated the important relevance of substituting dietary andamp;ugrave;-3 fatty acids such as andamp;aacute;-linolenic acid for andamp;ugrave;-6 fatty acid such as linoleic acid in reducing cardiovascular diseases.