Flow loading induces macrophage antioxidative gene expression in experimental aneurysms.
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.


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. alpha-Tocopherol was found to be as effective as flow loading in limiting AAA enlargement. Flow loading and alpha-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.
Nakahashi
Takeshi K
TK
Veterans Affairs Palo Alto Health Care System, Palo Alto, USA.
Hoshina
Katsuyuki
K
Tsao
Philip S
PS
Sho
Eiketsu
E
Sho
Mien
M
Karwowski
John K
JK
Yeh
Cory
C
Yang
Ruey-Bing
RB
Topper
James N
JN
Dalman
Ronald L
RL
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001164:Arteriovenous Fistula / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005263:Femoral Artery / Q000201:enzymology / Q000378:metabolism; D005268:Femoral Vein / Q000201:enzymology / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D018056:Hemorheology / Q000379:methods*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D024502:alpha-Tocopherol / Q000627:therapeutic use
D000975:Antioxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D024502:alpha-Tocopherol