Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation

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.

Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm

“…Our data allow us to speculate that the COX-2/mPGES-1/EP-4 axis in MVEC is relevant for the PGE 2 -mediated hypervascularization of AAA from the early stages of human AAA development. Our data are also consistent with reports showing that suppression of either COX-2, mPGES-1, or EP-4 expression reduces AAA development in animal models ( 15,16,19,20 ), and reinforce the potential of mPGES-1 and EP-4 as alternative targets for therapy in AAA patients. modest increase of mPGES-1 found in AAA is the breakdown of VSMCs in AAA.…”

“…EP-2 and EP-4 are both Gs-protein coupled receptors that upregulate intracellular cAMP levels, whereas EP-3 usually counteracts EP-2-and EP-4-mediated upregulation of cAMP by preferentially coupling to Gi proteins ( 17 ). Recently, confl icting results have been reported on the role of EP-4 in AAA development in animal models (18)(19)(20). These studies have been focused on the involvement of EPs in the activation of leukocytes (mainly macrophages) and VSMCs, and in the release of proteases during the immuneinfl ammatory process associated to AAA.…”

“…Main data regarding COX-2-alternative targets for the development of new anti-infl ammatory drugs for AAA comes from studies in animal models ( 16,(18)(19)(20). In these models, AAA develops fast and its etiology differs substantially from human pathology.…”

Prostaglandin E 2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling

“…In our previous report, analyses of human aortic aneurysmal tissues demonstrated that EP4 expression is greater in aneurysmal legions than that in nondiseased areas. 49 Further studies are required to investigate whether EP4-mediated LOX regulation plays a role in pathological conditions.…”

“…In our previous report, analyses of human aortic aneurysmal tissues demonstrated that EP4 expression is greater in aneurysmal legions than that in nondiseased areas. 49 Further studies are required to investigate whether EP4-mediated LOX regulation plays a role in pathological conditions.Taken together, these findings suggest that PGE 2 -EP4 signaling inhibits elastogenesis in the DA by degrading LOX protein.The PGE 2 -EP4-mediated LOX protein regulation via a previously unrecognized signaling pathway may also provide the basis for therapeutic strategies that target vascular elastogeneis. …”