Inhibition of EP4 signaling attenuates aortic aneurysm formation

• Published in: PloS one 2012-05, Vol.7 (5), p.e36724
• Main Authors: Yokoyama, Utako, Ishiwata, Ryo, Jin, Mei-Hua, Kato, Yuko, Suzuki, Orie, Jin, Huiling, Ichikawa, Yasuhiro, Kumagaya, Syun, Katayama, Yuzo, Fujita, Takayuki, Okumura, Satoshi, Sato, Motohiko, Sugimoto, Yukihiko, Aoki, Hiroki, Suzuki, Shinichi, Masuda, Munetaka, Minamisawa, Susumu, Ishikawa, Yoshihiro
• Format: Article
• Language: English
• Subjects: Abdomen; Activation; Aged; Aged, 80 and over; Aneurysm; Aneurysms; Angiotensin; Angiotensin II; Angiotensin II - adverse effects; Angiotensins; Animal models; Animal tissues; Animals; Aorta; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aortic Aneurysm, Abdominal - genetics; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - prevention & control; Aortic aneurysms; Apolipoprotein E; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Attenuation; Biology; Bone marrow; Calcium chloride; Cell Line; Chemokines; Cytokines; Degradation; Disease Models, Animal; Enzyme Activation - drug effects; Enzymes; EP4 protein; Extracellular matrix; Female; Gelatinase A; Gelatinase B; Gene Deletion; Geriatrics; Humans; Inflammation; Inhibition; Interleukin; Interleukin 6; Interleukin-6 - biosynthesis; Interleukins; Life sciences; Lymphoma; Macrophages; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase Inhibitors; Medical treatment; Medicine; Metalloproteinase; Mice; Mice, Knockout; Middle Aged; Monocyte chemoattractant protein 1; Muscles; Myocytes, Smooth Muscle - metabolism; Naphthalenes - pharmacology; Older people; Oral administration; Pharmaceutical industry; Pharmacology; Phenylbutyrates - pharmacology; Prostaglandin E2; Protein folding; Receptors, Prostaglandin E, EP4 Subtype - antagonists & inhibitors; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Signal Transduction - drug effects; Signaling; Smooth muscle; Stimulation; Studies; Surgery; Tissue Culture Techniques; University graduates; Up-Regulation - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0036724

Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. Immunohistochemical 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), PGE(2) 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