Abstract
BackgroundAortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA.Methods and FindingsImmunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE−/− mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01–0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45–87% reduction, P<0.05). Similarly, EP4+/−/ApoE−/− mice exhibited significantly less AAA formation than EP4+/+/ApoE−/− mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/− mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10–100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release.ConclusionAn EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.
Highlights
Aortic aneurysm is the 13th leading cause of death in the United States, with roughly 15,000 deaths per year [1]
An EP4 antagonist that prevents the activation of matrix metalloproteinase (MMP) and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of abdominal aortic aneurism (AAA)
In human tissue samples obtained from AAA surgeries, we found that EP4 expression and elastic fiber degradation were both enhanced in aneurysmal areas relative to that in normal areas
Summary
Aortic aneurysm is the 13th leading cause of death in the United States, with roughly 15,000 deaths per year [1]. Ultrasonography screening studies of men over 60 years old have shown that a small abdominal aortic aneurysm (AAA), i.e., 3 to 5 cm in diameter, is present in 4% to 5% of patients [2,3]. When patients with a small AAA were followed for up to 6 years, AAA diameter had increased in 55% of patients. The rate of increase in diameter was more than 1 cm per year in 23% of patients, and AAA diameter had expanded to 6 cm in 9% of patients, at which point the risk of rupture significantly increases [3]. AAAs typically continue to expand, increasing the likelihood of rupture and consequent mortality, no effective pharmacological therapy to prevent the progression of AAA is currently available. Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA
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