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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:2017.)
© 2002 American Heart Association, Inc.

Vascular Biology

Flow Loading Induces Macrophage Antioxidative Gene Expression in Experimental Aneurysms

Takeshi K. Nakahashi; Katsuyuki Hoshina; Philip S. Tsao; Eiketsu Sho; Mien Sho; John K. Karwowski; Cory Yeh; Ruey-Bing Yang; James N. Topper; Ronald L. Dalman

From the Veterans Affairs Palo Alto Health Care System, Palo Alto; Divisions of Vascular Surgery and Cardiology (P.S.T.), Stanford University; and Millennium Pharmaceuticals, Inc (R.-B.Y., J.N.T.), South San Francisco, Calif.

Correspondence to Ronald L. Dalman, 3801 Miranda Ave, B3-119, Palo Alto, CA 94304. E-mail rld{at}stanford.edu

Objective— Reactive oxygen species may act as proinflammatory mediators in abdominal aortic aneurysm (AAA) disease. Flow loading increases antioxidative enzyme expression and limits reactive oxygen species production in vascular smooth muscle cells in vitro, limits experimental AAA enlargement in rodent models, and is indirectly associated with reduced clinical AAA risk. We attempted to determine the mechanism or mechanisms by which flow loading limits AAA enlargement.

Methods and Results— Rodent AAAs were flow loaded via femoral arteriovenous fistula creation. Aortic wall shear stress and relative wall strain were significantly higher in flow-loaded rodents. Flow loading reduced AAA diameter by 26% despite evidence of flow-mediated aortic enlargement proximal to the aneurysmal segment. Messenger RNA from AAA tissue was harvested for cDNA labeling and hybridization to a 384-clone DNA microarray. Twenty-nine genes were differentially expressed (relative intensity/relative intensity of control ratio >1.5 and <0.67) in flow-loaded compared with normal flow AAA tissue, including heme oxygenase 1 (HO-1). Increased HO-1 expression was confirmed via reverse transcriptase–polymerase chain reaction. Immunohistochemistry localized HO-1 expression to infiltrative macrophages. -Tocopherol was found to be as effective as flow loading in limiting AAA enlargement. Flow loading and -tocopherol therapy reduced AAA reactive oxygen species production.

Conclusions— Flow loading may attenuate AAA enlargement via wall shear or strain-related reductions in oxidative stress.

Key Words: abdominal aortic aneurysm • alpha-tocopherol • reactive oxygen species • heme oxygenase 1 • shear stress

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