Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms.
BACKGROUND
Abdominal aortic aneurysms (AAAs) involve an unfavorable balance between the destruction and the repair of connective tissue proteins. The purpose of this study was to assess the functional importance of connective tissue repair during experimental aneurysmal degeneration.


METHODS
Male Wistar rats (n = 70) underwent transient intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase. In Study I, the aortic diameter was measured before elastase perfusion and at days 0, 2, 7, and 14 (n = 6 rats at each interval). Aortic wall concentrations of desmosine (Des) and hydroxyproline (OHP) were measured at each interval, and the expression of tropoelastin (TE), alpha1(I) procollagen (PC), and lysyl oxidase genes was evaluated by reverse transcription-polymerase chain reaction. In Study II, 22 rats were treated with beta-aminopropionitrile (BAPN) to block connective tissue repair. In Study III (n = 30), rats were treated with doxycycline, a matrix metalloproteinase inhibitor, beginning 7 days after elastase perfusion.


RESULTS
AAAs consistently developed between 7 and 14 days after elastase perfusion. Aortic wall Des concentration decreased markedly during aneurysm development, reaching 3% of normal by day 14 (377 +/- 22 pmol of Des/sample on day 0 vs 9 +/- 1 pmol of Des/sample on day 14; P <.05). Aortic wall OHP decreased to only 68% of normal at the same interval (121 +/- 10 nmol of OHP/sample on day 0 vs 82 +/- 14 nmol of OHP/sample on day 14; P <.05). TE and PC expression was undetectable in healthy aorta, but they both increased by day 7 (P <.05); while TE expression decreased again by day 14, PC continued to rise. Lysyl oxidase expression progressively decreased at all intervals after elastase perfusion. Treatment with beta-aminoproprionitrile resulted in acute aortic dissection in 81% of the rats (50% mortality). These early deaths occurred between days 3 and 6, coinciding with aortic infiltration by proteinase-secreting inflammatory cells. Delayed treatment with doxycycline suppressed the progression of aneurysmal dilatation between days 7 and 21 (P <.05 vs untreated controls).


CONCLUSIONS
The development of elastase-induced AAAs is accompanied by an active process of connective tissue repair. While this reparative process is necessary to stabilize the developing aneurysm wall, it is insufficient to prevent aneurysm progression. In contrast, reducing the proteolytic destruction of connective tissue proteins promotes stabilization of the aneurysmal aorta.
Huffman
M D
MD
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
Curci
J A
JA
Moore
G
G
Kerns
D B
DB
Starcher
B C
BC
Thompson
R W
RW
D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000503:physiopathology*; D003238:Connective Tissue / Q000187:drug effects / Q000503:physiopathology*; D003895:Desmosine / Q000032:analysis; D006909:Hydroxyproline / Q000032:analysis; D008297:Male; D010196:Pancreatic Elastase; D011347:Procollagen / Q000235:genetics; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014333:Tropoelastin / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects
D011347:Procollagen; D014333:Tropoelastin; D003895:Desmosine; D000629:Aminopropionitrile; D008249:Protein-Lysine 6-Oxidase; D010196:Pancreatic Elastase; D006909:Hydroxyproline