Rosiglitazone Reduces the Development and Rupture of Experimental Aortic Aneurysms

Abstract

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...

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

“…A recent study by Cassis et al ( 20 ) demonstrated that Ang II infusionpromoted AAA formation was independent of increases in blood pressure . Some other agents, like vitamin E and rosiglitazone, exhibited inhibitory effects on Ang II-induced AAA formation without altering the blood pressure ( 16,35 ). Moreover, the s-EH inhibitor AR9276 did not reduce blood pressure in this AAA model ( 14 ).…”

“…EETs activate PPAR ␥ ( 15 ), and PPAR ␥ activation is associated with AAA development ( 16,44 ). Studies showed that VSMC PPAR ␥ deletion promotes AAA ( 44 ), and the administration of the PPAR ␥ agonist, rosiglitazone, prevents AAA progression ( 16 ).…”

“…AAAs were induced in ApoE Ϫ / Ϫ mice by a 28 day continuous Ang II (1,000 ng/kg/min) (Sigma-Aldrich, St. Louis, MO) infusion by subcutaneous osmotic pump implantation as described previously ( 16,20 ). Thirty-two 8-week-old ApoE Ϫ / Ϫ mice were randomly assigned into 4 groups: control group (n = 8), receiving saline; Ang II group (n = 8), receiving Ang II (1000 ng/ kg/min); Ang II + rAAV-GFP group (n = 8), receiving Ang II (1,000 ng/kg/min) infusion supplemented with rAAV-GFP injection; and Ang II + rAAV-CYP2J2 group, receiving Ang II (1,000 ng/kg/min) infusion supplemented with rAAV-CYP2J2 injection.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…TGF-b-dependent changes during aneurysm development include increased expression and/or activities of matrix-degrading enzymes such as metalloproteinases, degradation of elastic fibers, enhanced proliferation and migration of VSMCs, and excessive collagen secretion and deposition (reviewed in Jones et al 2009). Overall, the effects of these alterations, which target both matrix degradation and matrix deposition, weaken the aortic wall rendering it more prone to dilatation, dissection, and rupture.…”

Role of Peroxisome Proliferator-Activated Receptor-.GAMMA. in Atherosclerosis - An Update -

“…Rosiglitazone reduced aortic expansion and rupture in Ang II-infused ApoE -/-mice along with a suppression of Ang II type A receptor, TNFα, IL-6 and E-selectin. 90 Reduction of lesions in animals pretreated with rosiglitazone is concomitant with decreased expression of inflammatory mediators. Using transplantation of vessels from PPARγ knock-out mice, Hamblin et al demonstrated that loss of PPARγ in vascular SMCs promoted aortic dilatation and elastin degradation and identified cathepsin S as a target gene for PPARγ, suggesting PPARγ as an important contributor in attenuating the development of aortic aneurysms.…”