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...

Our findings suggest that increased COX-2 expression in smooth muscle cells of the abdominal aorta contributes to AAA formation in mice by enhancing inflammatory cell infiltration.

Rho kinases (ROCKs) are serine-threonine protein kinases that regulate the actin cytoskeleton. Recent studies suggest that ROCKs also play an important role in cardiovascular disease. However, the isoform- and tissue-specific role of ROCKs in mediating this process is unknown. Using homologous recombination, we generated mutant mice harboring alleles with homozygous deletion of ROCK1 (ROCK1(-/-)). Most ROCK1(-/-) mice die perinatally. However, a few ROCK1(-/-) mice survive to adulthood, are phenotypically normal, and have no apparent compensatory changes in ROCK2. Using these ROCK1(-/-) mice, we show that ROCK1 in bone marrow-derived macrophages is critical to the development of atherosclerosis, in part, by mediating foam cell formation and macrophage chemotaxis. Lipid accumulation and atherosclerotic lesions were reduced in atherosclerosis-prone LDLR(-/-) mice, whose bone marrows have been replaced with bone marrows derived from ROCK1(-/-) mice. Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low-density lipoprotein. These findings indicate that ROCK1 in bone marrow-derived cells is a critical mediator of atherogenesis and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.

The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.