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

• Published in: Physiological reports 2018-09, Vol.6 (18), p.e13878-n/a
• Main Authors: Mamun, Al, Yokoyama, Utako, Saito, Junichi, Ito, Satoko, Hiromi, Taro, Umemura, Masanari, Fujita, Takayuki, Yasuda, Shota, Minami, Tomoyuki, Goda, Motohiko, Uchida, Keiji, Suzuki, Shinichi, Masuda, Munetaka, Ishikawa, Yoshihiro
• Format: Article
• Language: English
• Subjects: Abdomen; Abdominal aortic aneurysm; Aging; Aneurysms; Angiotensin; Angiotensin II; Animal models; Animals; Aorta, Abdominal - drug effects; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - drug therapy; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Aortic aneurysms; Apolipoprotein E; Apolipoproteins E - deficiency; Arthritis; Calcium chloride; Cardiovascular disease; Cells, Cultured; Cellulose; Coronary vessels; elastic fiber, interleukin‐6; EP4; Humans; Laboratory animals; Male; Matrix metalloproteinase; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Oral administration; Original Research; Physiology; Prostaglandin E; Prostaglandin E2; Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Smooth muscle; Studies; Sulfonylurea Compounds - pharmacology; Sulfonylurea Compounds - therapeutic use
• ISSN: 2051-817X
• DOI: 10.14814/phy2.13878

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 PGE2‐induced IL‐6 secretion in a dose‐dependent manner and decreased PGE2‐induced MMP‐2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression. No effective pharmacological therapy to attenuate AAA progression is currently available. Here, we show the beneficial 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). These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.