Selective Cyclooxygenase-2 Inhibition With Celecoxib Decreases Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice

Abstract

Objective-Inflammation plays an integral role in the development of abdominal aortic aneurysms (AAAs), and the expression of cyclooxygenase (COX)-2 is increased in aneurysmal tissue compared with normal aorta. Nonsteroidal anti-inflammatory drugs, which inhibit the activity of COX-1 and COX-2, decrease AAA expansion in humans and animal models of the disease. In the current study, we investigated the effectiveness of selective inhibition of COX-1 or COX-2 in attenuating AAA formation. Methods and Results-Eight-week-old male apolipoprotein E-deficient mice were treated with selective inhibitors of COX-1 or COX-2, SC-560 (Ϸ25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1), or celecoxib (Ϸ125 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), respectively. COX inhibitors were administered 1 week before angiotensin II (Ang II; 1000 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or saline infusion and throughout the time course of the experiment. COX-1 inhibition had no effect on incidence (control: 90% [9:10] versus ) or severity of Ang II-induced AAA formation. In contrast, celecoxib decreased the incidence (control: 74% Key Words: cyclooxygenase-1 Ⅲ cyclooxygenase-2 Ⅲ abdominal aortic aneurysms Ⅲ celecoxib Ⅲ prostaglandin E 2 A bdominal aortic aneurysms (AAAs) are an increasing health concern, particularly in the male population Ͼ65 years of age. AAAs are a permanent dilation of the artery leading to extensive remodeling of the vessel wall with a potential for rupture and resulting mortality. Hallmarks of AAAs are proteolytic degradation and the presence of an inflammatory infiltrate within the vascular wall. 1 Inflammatory cells within the vascular wall are a significant source of proteolytic enzymes that contribute to the disease. 1,2 Thus, a putative cause of human AAAs may be cellular remodeling within the vascular wall resulting from chronic inflammation and matrix degradation. See page 956Prostanoids are a class of inflammatory mediators that are dramatically increased in aneurysmal tissue. [3][4][5] Prostanoids, which include prostaglandins and thromboxane A 2 , are synthesized by the 2 known isoforms of prostaglandin G/H synthase, also known as cyclooxygenase (COX)-1 and COX-2. 6 -8 COX-1 is constitutively expressed in most tissues, whereas COX-2 expression is inducible and is primarily responsible for the synthesis of prostanoids that contribute to inflammation. 6 -8 COX-2 expression is induced during the development of aneurysms, whereas, COX-1 expression is not altered, suggesting a primary role for COX-2 in the development of this disease. [3][4][5] Although a variety of inflammatory cells are present in aneurysmal tissue, macrophages are believed to have a pronounced role in the pathogenesis of AAAs. 2,9,10 Activated macrophages within the inflammatory infiltrate of human AAAs are a significant source of COX-2 expression, which may be responsible for the synthesis of prostanoids contributing to the vascular inflammation. 4,5 The prostanoid most often observed in human aneurysmal tissue is prostaglandin E 2 (PGE 2 ). 4,5 PGE 2 synthesized by macrophages and smooth muscle cells (S...

COX-2 in Cardiovascular Disease

“…20 Furthermore, NSAID use is associated with a reduction in abdominal aortic aneurysm expansion. 16,17 In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, King et al 21 investigate the roles of COX-1 and COX-2 in a model of abdominal aortic aneurysm. Abdominal aortic aneurysms are caused by local permanent dilation, leading to tissue remodelling, weakening, and the potential of rupture.…”

“…In man, abdominal aortic aneurysms demonstrate pronounced local inflammation and contain high levels of COX-2, PGE 2 , and proteolytic enzymes. Using a murine model of angiotensin II-induced abdominal aortic aneurysm, King et al 21 show that selective inhibition of COX-2 with oral dosing of celecoxib dramatically reduced the incidence (control, 74%; celecoxib-treated, 11%) and severity of abdominal aortic aneurysms in apoE Ϫ/Ϫ knockout mice. Inhibition of COX-1 using the COX-1-selective inhibitor SC560 was without effect.…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Some evidence has suggested that CCL5 also has an important role in Ang II induced dissecting AAA [41]. Moreover, Ang II may stimulate the expression of cyclooxygenase-2 (COX-2) [42,43], a critical enzyme in AAA pathogenesis that forms vasoactive and inflammatory prostaglandins. Indeed, it has been shown that COX-2 deficiency attenuates Ang II infusion-mediated dissecting AAA [44].…”

Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

“…King at al. 61 studied nonsteroidal anti-inflammatory drugs (NSAID), which inhibit the activity of COX-1 and COX-2, to evaluate the effect in an angII-induced AAA mouse model. They noted celecoxib decreased the incidence and severity of AAA formation in both hyperlipidemic and nonhyperlipidemic mice.…”