Transient exposure to elastase induces mouse aortic wall smooth muscle cell production of MCP-1 and RANTES during development of experimental aortic aneurysm.
OBJECTIVE
Abdominal aortic aneurysm (AAA) is associated with chronic transmural inflammation and destruction of the elastic media. The purpose of this study was to elucidate molecular mechanisms that might orchestrate leukocyte recruitment into the outer aortic wall by determining whether CC chemokines contribute to development of aneurysm degeneration in an elastase-induced mouse model of AAA.


METHODS
Adult male C57BL/6J mice underwent transient elastase perfusion of the abdominal aorta to induce development of AAA. At various intervals after elastase perfusion (0, 4, 7, 14 days), real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to measure aortic wall expression of the CC (beta) chemokines, monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T-cell expressed and secreted (RANTES). Expression of these chemokines by cultured mouse aortic smooth muscle cells (AoSMC) was similarly assessed after transient (5 minutes) exposure to elastase solutions in vitro.


RESULTS
Mouse aortic diameter (mean +/- SEM) increased to aneurysmal proportions by 14 days after elastase perfusion (from 0.51 +/- 0.03 mm to 1.34 +/- 0.32 mm; 163% increase; P <.05), with macrophage infiltration of the outer aortic wall beginning within 7 to 10 days. Increased aortic wall messenger RNA expression for MCP-1 (28-fold) and RANTES (11-fold) was observed on day 4, with maximal production of chemokine protein on day 7 (MCP-1, from 7.07 +/- 0.06 ng/mL to 19.60 +/- 0.19 ng/mL; P <.001; RANTES, from 0.23 +/- 0.006 ng/mL to 2.03 +/- 0.057 ng/mL; P <.001). Neither MCP-1 nor RANTES was detected in normal mouse aorta with immunohistochemistry, but both chemokines were abundant in AAA. Within 48 hours of transient exposure to elastase, cultured mouse AoSMC exhibited pronounced induction (>90-fold) of MCP-1 and RANTES, despite concomitant decrease in cell numbers.


CONCLUSIONS
Increased mouse aortic wall expression of MCP-1 and RANTES occurs early in development of elastase-induced AAA and before onset of the chronic inflammatory response. Moreover, elastase directly stimulates AoSMC chemokine production in vitro. Elastase-induced medial SMC production of CC chemokines may therefore provide an important link between enzymatic injury, leukocyte recruitment, and aneurysmal degeneration of the aortic wall.
Colonnello
Jamie S
JS
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Hance
Kirk A
KA
Shames
Murray L
ML
Wyble
Charles W
CW
Ziporin
Scott J
SJ
Leidenfrost
Jeremy E
JE
Ennis
Terri L
TL
Upchurch
Gilbert R
GR
Thompson
Robert W
RW
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D019742:Chemokines, CC / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000494:pharmacology*
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D010196:Pancreatic Elastase