Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation.

Abstract

OBJECTIVE:

To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo.

METHODS AND RESULTS:

Prostaglandin E(2) (PGE(2)) through activation of EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR(-/-)) mice transplanted with either EP4(+/+) (EP4(+/+)/LDLR(-/-)) or EP4(-/-) (EP4(-/-)/LDLR(-/-)) bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow-derived cells increased the incidence (50% of male EP4(+/+)/LDLR(-/-) mice versus 88.9% of male EP4(-/-)/LDLR(-/-) mice developed AAA; and 22% of female EP4(+/+)/LDLR(-/-) mice versus 83.3% of female EP4(-/-)/LDLR(-/-) mice developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow-derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth muscle cell accumulation within AAA lesions.

CONCLUSIONS:

Deficiency of EP4 on bone marrow-derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE(2) signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation.

• Authors: Eva H C Tang, Eugenia Shvartz, Koichi Shimizu, Viviane Z Rocha, Chunyu Zheng, Daiju Fukuda, Guo-Ping Shi, Galina Sukhova, Peter Libby
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 2 Pg. 261-9 (Feb 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21088251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Ptger4 protein, mouse
• Receptors, LDL
• Receptors, Prostaglandin E, EP4 Subtype
• Angiotensin II
• Elastin

Topics

• Angiotensin II (adverse effects)
• Animals
• Aortic Aneurysm, Abdominal (chemically induced, epidemiology, metabolism)
• Bone Marrow Cells (cytology, metabolism)
• Bone Marrow Transplantation
• Chemokine CCL2 (metabolism)
• Elastin (metabolism)
• Female
• Gene Deletion
• Hyperlipidemias (complications, metabolism)
• Inflammation (chemically induced, epidemiology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Receptors, LDL (genetics, metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (genetics, metabolism)
• Risk Factors