Background-Development and rupture of aortic aneurysms involve a combination of complex biological processes.Rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist, has been shown to have a broad spectrum of effects in vivo. The hypothesis that rosiglitazone would reduce aneurysm expansion or rupture was tested in the angiotensin II (Ang II)-induced hypercholesterolemic mouse model. Methods and Results-Apolipoprotein E-deficient mice, 12 months of age, were allocated to 4 groups. Three groups were infused with Ang II (1 g · min Ϫ1 · kg Ϫ1 ), and the fourth was infused with saline. Rosiglitazone was given 1 week before infusion and 1 week after infusion. At day 28, aortic size was measured, and tissues were collected for analyses. Both pretreatment and posttreatment with rosiglitazone inhibited the occurrence of fatal rupture (11 of 30 versus 0 of 30 versus 0 of 15; Pϭ0.0013) and reduced maximal dilatation of the aorta (4.6Ϯ0.13 versus 2.4Ϯ0.48 versus 2.15Ϯ0.46 mm 2 ; PϽ0.0001). Blood glucose, total cholesterol, body weight, and atherosclerosis did not differ between groups. Pretreatment with rosiglitazone inhibited the Ang II-induced expression of angiotensin type 1a Ang II receptor while having no effect on the angiotensin type 2 Ang II receptor, in addition to reducing Ang II-induced expression of E-selectin, tumor necrosis factor-␣, and interleukin-6. Key Words: aneurysm Ⅲ aneurysm, ruptured Ⅲ angiotensin Ⅲ inflammation Ⅲ polymerase chain reaction Ⅲ PPAR gamma R upture of an aortic aneurysm is the third-commonest cause of sudden death after myocardial infarction and stroke. Approximately 5% of men Ͼ60 years of age will develop an abdominal aortic aneurysm. Currently, the only treatment option for patients with aneurysms is surgical repair when the aneurysm expands past a critical point (usually a diameter threshold of 5.5 cm). Screening programs have begun to identify a large number of patients with small aortic aneurysms who would benefit from targeted pharmacotherapy to reduce aneurysm expansion and rupture. Conclusions-Pretreatment Clinical Perspective on p 3132Any potential pharmacological strategy to modulate the natural history of the aneurysmal process must be targeted to the biological process that mediates aneurysm expansion and rupture. Much of our understanding of the human pathogenesis of abdominal aortic aneurysm, obtained from analysis of aneurysmal biopsies during open surgery, is limited to analysis of the end-stage disease. Histological examination has identified that degeneration of the medial elastic fibers and compensatory deposition of collagens are accompanied by adventitial hypertrophy and infiltration of macrophages and T and B lymphocytes. Atherosclerosis and thrombus formation also are features of abdominal aortic aneurysm. [1][2][3][4] It is most likely that the dynamic remodeling process mediating the vascular changes observed in aneurysm development is the result of an initial inflammatory response. Involvement of inflammation as an instigating mechanism has been co...

Abdominal aortic aneurysm (AAA) rupture is associated with elevated levels of matrix metalloproteinase (MMP). Medial neovascularization is a known characteristic of established AAAs and involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell proliferation and migration. This study evaluated the extent of neovascularization in abdominal aortic aneurysm rupture. Results indicated upregulation of proangiogenic cytokines and increased medial neovascularization at the aneurysm rupture edge compared with paired aneurysm anterior sac. Further investigations into the role of angiogenesis in aneurysm rupture may open novel therapeutic avenues to prevent aneurysm rupture.

To search for novel transcriptional pathways that are activated in abdominal aortic aneurysm rupture, cDNA microarrays were used to compare global mRNA expression at the aneurysm rupture edge to anterior sac, and selected results were confirmed using quantitative real-time-polymerase chain reaction (QRT-PCR). This study identified apoptosis, angiogenesis, and inflammation as potentially important participants during the process of aneurysm rupture.

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Background: Multiple infusions of HDLs have been shown to mediate approximately 4% reduction in plaque volume. This may relate to removal of intra-plaque lipid, but the precise mechanism is unknown. To test the hypothesis that HDLs may influence plaque stabilisation through modulating transcription, we examined the effects of a single dose of rHDL on expression of thrombomodulatory genes in carotid plaques. Materials and Methods: Forty patients undergoing carotid endarterectomy (CEA) were stratified to three groups: early symptomatics ( n =12, stroke/transient ischemic attack (TIA) 1month before CEA)late symptomatics ( n =14, stroke/TIA > 1month before CEA); and asymptomatics ( n =12). RNA was isolated from plaques following CEA, and expression of the thrombomodulatory genes, tissue factor (TF); tissue factor pathway inhibitor (TFPI); thrombomodulin (TM); tissue type plasminogen activator (tPA); urokinase plasminogen activator (uPA); plasminogen activator inhibitor-1 (PAI-1), measured using QRT-RT-PCR. Nine patients with early symptomatic carotid disease, undergoing CEA, were then randomised to infusion of reconstituted HDL (rHDL) 80mg/kg Apo A-I ( n =4) or a similar volume of phosphate buffered saline ( n =5). Plaque specimens were collected 24 hrs later and RNA isolated for QRT-RT- PCR measurement of thrombomodulatory gene expression. Results: A significant difference in TF, TM, tPA and PAI-1 genes were observed in the 3 patient groups (see Table 1 ). In the rHDL group, a single dose of rHDL reduced the expression of TF (0.71 (0.65–0.75) vs 0.98 (0.81–1.14), P=0.05). No significant difference was observed in other thrombomodulatory factors between the 2 groups. Conclusions: Plaque stabilisation, which occurs within one month of a clinical event may be facilitated, at the transcriptional level, following rHDL infusion. We hope to report a larger double blind placebo controlled trial which will determine the full effects of rHDLs on plaque stability. Table 1

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