Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 158-162).

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

No description available.

Adipocytes express angiotensin II (AngII) receptors; however the direct effects of AngII at the adipocyte remain unclear. Knockout mouse models of renin-angiotensin system components exhibit reduced body weight, reduced adiposity, improved glucose tolerance, and improved blood pressure when fed high fat diets, which may be due to reduced action of AngII through the AT1aR in adipocytes. Additionally, hypercholesterolemic AT1aR deficient mice are protected from AngII-induced increases in atherosclerosis and abdominal aortic aneurysm (AAA) formation. We hypothesized that deficiency of AT1aR in adipocytes would reduce the development of obesity, obesity-induced disorders, and vascular diseases. To test this hypothesis, we created a mouse model of adipocyte AT1aR deficiency using the Cre/LoxP system. Adipocyte-AT1aR deficiency confers no protection from the development of obesity or obesity- associated parameters. However, low fat fed adipocyte-AT1aR deficient mice exhibit remarkable adipocyte hypertrophy and reductions in adipocyte differentiation. These results demonstrate that AngII is a stimulus for adipocyte differentiation and adipocyte hypertrophy alone is insufficient to initiate obesity- associated disorders. In hypercholesterolemic mice, adipocyte AT1aR deficiency conferred no protection from diet or AngII-induced vascular diseases. Overall these studies suggest the primary role of adipocyte AT1aRs is to promote adipocyte differentiation and the development of small adipocytes.

A previous thoracic aortic aneurysm time course study from our laboratory determined that ascending aortic dilation was significantly increased by day 5, and reached a plateau by day 28 of angiotensin II (AngII) infusion. We also found that mice had hemorrhage localized to the ascending aortas by day 5 of AngII infusion. The purpose of these studies was to provide mechanistic insight into the development of AngII-induced ascending aortic hemorrhage. Male C57BL/6 mice fed normal diet were subcutaneously infused with either AngII (1000 ng/kg/min) or saline for 5 days. To examine cellular heterogeneity, hemorrhaged ascending aortas were collected and sectioned serially for histological staining and immunostaining. I was unable to identify an entry point for blood into the media of the aortic root and ascending aorta. However, I found incomplete intimo-medial dissection near the hemorrhaged regions that may potentially be contiguous with the blood. To investigate infiltration of immune cells during AngII infusion, immunohistochemistry of hemorrhaged ascending aortas was performed. The numbers of macrophages and neutrophils in AngII-infused aortas were increased in both medial and adventitial areas when compared with saline-infused aortas. Therefore, infiltration of immune cells at the point of dissection is associated with aortic hemorrhage during AngII infusion.

The occurrence of clinically diagnosed and/or ruptured abdominal aortic aneurysms (AAAs) in the families of 220 patients with AAAs, treated at the Surgical Clinic, University Hospital of Umeå in the northern part of Sweden during the years 1965-82, was studied. A questionnaire concerning the blood relatives was answered by 87/89 patients. 16/87 patients (18%) had blood relatives with AAAs. In 14 families one blood relative was affected, and in 2 families two blood relatives were affected. First degree relatives were affected in 9/87 cases (10%), and second degree relatives in 7/87 cases (8%). 9/468 (1.9%) of the patients' brothers and sisters but only five of all their cousins had AAAs, and 7/204 (3.4%) of the dead brothers and sisters had died of ruptured AAAs. Concerning the patients who were not included in the letter survey at least 14/133had blood relatives with AAAs. However, the great majority of these patients were dead when the study was performed and could not be asked aboutthe occurrence of AAAs in their families. The patients with AAAs had significantly higher serum concentrations of triglyceride and (YLDL + LDL)-cholesterol and a significantly lower serum concentration of HDL-cholesterol than randomly selected healthy controls of the same sex and age as the patients. We also compared the distributions of genetic markers (HLA antigens, the blood group systems ABO, Rh, MNSs, P, Kell, Lewis and Duffy and the serum protein group systems haptoglobin, transferrin, group-specific component, complement C3, properdin factor and alpha-1-antitrypsin) in patients with AAAs with the distributions in controls and in some cases with the expected distributions according to the Hardy-Weinberg law. A significantly decreased frequency of Rh-negative individuals, and significantly increased frequencies of Kell-positi ve individuals, of MN heterozygotes and of heterozygotes concerning haptoglobin type was found. Furthermore, the aneurysm walls of patients with and without AAAs in the family were compared concerning the morphology, but no differences were found. We also studied the occurrence of collagen types I and III in the aneurysm walls, and the occurrence of vimentin and desmin in the smooth muscle cells of the aneurysm walls, but all these components were present in the aneurysm walls of both the patients with and those without AAAs in the family. To summarize the results, there seems to be an increased frequency of AAAs, and especially of ruptured AAAs, among the brothers and sisters of patients with AAAs. Elevated serum concentrations of triglyceride and (VLDL + LDL)- cholesterol and a lowered serum concentration of HDL-cholesterol seems to be common in patients with AAAs. There seems to be a hereditary predisposition to the development of AAAs, because we found associations with four different genetic markers (Rh, MN, Kell, haptoglobin group). However, there is probably no specific "familial" type of AAAs, because we found no differences between the patients with and those without AAAs in the family.Key words: / <p>S. 1-42: sammanfattning, s. 43-103: 5 uppsatser</p> / digitalisering@umu

Thesis (Ph. D.)--University of Houston, 2005. / Includes bibliographical references (leaves 100-110). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (Ph. D.)--University of Houston, 2005. / Includes bibliographical references (leaves 100-110).

No description available.