ArticlePloS one2012
Inhibition of EP4 signaling attenuates aortic aneurysm formation.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 72 citations in OpenAlex.
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- Prostanoids in Cardiac and Vascular Remodeling.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- Development of pharmacotherapies for abdominal aortic aneurysms.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Review
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- Acetylsalicylic Acid Is Associated With a Lower Prevalence of Ascending Aortic Aneurysm and a Decreased Aortic Expression of Cyclooxygenase 2.Journal of the American Heart Association · 2022Article
- Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation.Clinical science (London, England : 1979) · 2022Article
- Prostaglandin-E2 receptor-4 stimulant rescues cardiac malfunction during myocarditis and protects the heart from adverse ventricular remodeling after myocarditis.Scientific reports · 2021Article
- Suppression of Vascular Macrophage Activation by Nitro-Oleic Acid and its Implication for Abdominal Aortic Aneurysm Therapy.Cardiovascular drugs and therapy · 2021Article
- International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin EPharmacological reviews · 2020Article
- 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.Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery · 2020Review
- Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation.ESC heart failure · 2020Article
- AVE0991, a nonpeptide angiotensin-(1-7) mimic, inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E knockout mice.Journal of molecular medicine (Berlin, Germany) · 2020Article
- Prostaglandin ECancer science · 2020Article
- Inflammation increases MMP levels via PGEInternational journal of obesity (2005) · 2019Article
- Systems Approach to Study Associations between OxLDL and Abdominal Aortic Aneurysms.International journal of molecular sciences · 2019Article
- VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A selective antagonist of prostaglandin E receptor subtype 4 attenuates abdominal aortic aneurysm.Physiological reports · 2018Article
- Inhibition of prostaglandin E2 protects abdominal aortic aneurysm from expansion through regulating miR-29b-mediated fibrotic ECM expression.Experimental and therapeutic medicine · 2018Article
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 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. 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), 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<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 CaCl(2) 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.
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