A selective antagonist of prostaglandin E receptor subtype 4 attenuates abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression. Here, we show the effect of CJ‐42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II‐ and CaCl2‐induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. Oral administration of CJ‐42794 (0.2 mg/kg per day) for 4 weeks significantly decreased AAA formation in ApoE−/− mice infused with angiotensin II (1 μg/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)‐2 and MMP‐9 were attenuated. Interleukin‐6 (IL‐6) proteins were highly expressed in the medial layer of angiotensin II‐induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ‐42794. AAA formation induced by periaortic CaCl2 application in wild‐type mice was also reduced by oral administration of CJ‐42794 for 4 weeks. After oral administration of CJ‐42794 beginning 2 weeks after periaortic CaCl2 application and continuing for an additional 4 weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ‐42794‐treated mice than in untreated mice. Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ‐42794 inhibited PGE 2‐induced IL‐6 secretion in a dose‐dependent manner and decreased PGE 2‐induced MMP‐2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.

VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure

“…However, the role of EP4 in pathological vascular remodeling remains uncertain. It has been reported that inhibition of EP4 attenuates aortic aneurysm formation (10)(11)(12), whereas the lack of EP4 in hematopoietic cells is associated with increased prevalence and severity of AngII-induced aortic aneurysms (13).…”

Pulmonary artery aneurysm as a result of group 2 pulmonary artery hypertension in a patient with significant mitral and aortic valve disease – review and case report

“…In a Japanese study it was observed that the PA aneurysm area, in comparison to non-PAA areas, showed increased EP4 receptor (for the cyclooxygenase-2-dependent PGe2) expression [2]. The increased expression of that receptor is also described in non-striated muscle cells as well as in macrophages in abdominal aortic aneurysm areas [21][22][23]. PGe2, via the eP4 receptor, increases the activity of metalloproteinase 2 and the production of interleukin 6, causing increased degradation of elastic fibers redounding to the AAA progression [21,22].…”

“…The increased expression of that receptor is also described in non-striated muscle cells as well as in macrophages in abdominal aortic aneurysm areas [ 21 – 23 ]. PGE2, via the EP4 receptor, increases the activity of metalloproteinase 2 and the production of interleukin 6, causing increased degradation of elastic fibers redounding to the AAA progression [ 21 , 22 ]. Nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors suppress PGE2 synthesis.…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…In human AAA samples, higher EP4-receptor expression versus normal samples was demonstrated by real-time PCR studies (Camacho et al, 2013). Exposure of aortic smooth muscle cells (SMCs) and macrophages derived from human AAA preparations to EP4-receptor antagonists (CJ-42794 or ONO-AE3-208) decreased MMP activation and proinflammatory cytokines secretion (Cao et al, 2012;Yokoyama et al, 2012;Mamun et al, 2018). These findings suggested that EP4-receptor antagonists could be a therapeutic target for the treatment of AAA.…”

“…These findings suggested that EP4-receptor antagonists could be a therapeutic target for the treatment of AAA. Similarly, administration of EP4-receptor antagonist or deletion of the EP4 receptor in ApoE knockout mice reduced AAA formation via diminution of cytokine/chemokine levels and MMP activities ( Cao et al, 2012 ; Yokoyama et al, 2012 ; Mamun et al, 2018 ). However, there is one contradictory study performed in hyperlipidemic mice.…”