Urokinase-Type Plasminogen Activator Plays a Critical Role in Angiotensin II–Induced Abdominal Aortic Aneurysm

• Published in: Circulation research Vol. 92; no. 5; pp. 510 - 517
• Main Authors: Deng, Gary G, Martin-McNulty, Baby, Sukovich, Drew A, Freay, Ana, Halks-Miller, Meredith, Thinnes, Therese, Loskutoff, David J, Carmeliet, Peter, Dole, William P, Wang, Yi-Xin
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 21.03.2003; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Angiotensin II - pharmacology; Animals; Aorta - metabolism; Aorta - pathology; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Apolipoproteins E - genetics; Arteriosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the aorta; In Situ Hybridization; Interleukin-6 - secretion; Male; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger - metabolism; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - physiology; atherosclerosis; Animal model; u-Plasminogen activator; Serine endopeptidases; Pathophysiology; Enzyme; Deficiency; Rodentia; Aneurysm; Cardiovascular disease; Arterial disease; Vascular disease; Abdominal aorta; Peptidases; Vertebrata; Experimental disease; Mammalia; Mouse; urokinase-type plasminogen activator deficiency; Apolipoprotein E; Animal; Hydrolases; vascular inflammation
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000061571.49375.E1

ABSTRACT—We have previously demonstrated that urokinase-type plasminogen activator (uPA) is highly expressed in the aneurysmal segment of the abdominal aorta (AAA) in apolipoprotein E–deficient (apoE) mice treated with angiotensin II (Ang II). In the present study, we tested the hypothesis that uPA is essential for AAA formation in this model. An osmotic minipump containing Ang II (1.44 mg/kg per day) was implanted subcutaneously into 7- to 11-month-old male mice for 1 month. Ang II induced AAA in 9 (90%) of 10 hyperlipidemic mice deficient in apoE (apoE/uPA mice) but in only 2 (22%) of 9 mice deficient in both apoE and uPA (apoE/uPA mice) (P <0.05). Although the expansion of the suprarenal aorta was significantly less in apoE/uPA mice than in apoE/uPA mice, the aortic diameters of the aorta immediately above or below the suprarenal aorta were similar between the 2 groups. Ang II induced AAA in 7 (39%) of 18 strain-matched wild-type C57 black/6J control mice. The incidence was significantly higher in atherosclerotic apoE-deficient (apoE) mice, in which 8 (100%) of 8 mice developed AAA. Only 1 (4%) of 27 uPA mice developed AAA after Ang II treatment. We conclude the following(1) uPA plays an essential role in Ang II–induced AAA in mice with or without preexisting hyperlipidemia and atherosclerosis; (2) uPA deficiency does not affect the diameter of the nonaneurysmal portion of the aorta; and (3) atherosclerosis and/or hyperlipidemia promotes but is not essential for Ang II–induced AAA formation in this model.