Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms

Background. Abdominal aortic aneurysms (AAAs) involve an unfavorable balanc e between the destruction and the repair of connective tissue proteins. The purpose of this study was to assess the functional. importance of connecti ve tissue repair during experimental aneurysmal degeneration. Methods. Male Wistar rats (n = 70) underwent transient intraluminal perfusi on of the abdominal aorta with porcine pancreatic elastase. In Study I, the aortic diameter was measured before elastase per fusion and at days 0, 2, 7, and 14 (n = 6 rats at each interval). Aortic wall concentrations of desm osine (Des) and hydroxyproline (OHP) were measured at each interval, and th e expression of tropoelastin (TE), alpha 1(I) procollagen (PC), and lysyl o xidase genes was evaluated by reverse transcription-polymerase chain reacti on. In Study II, 22 rats were treated with beta-aminopropionitrile (BAPN) t o block connective tissue repair In Study III (n = 30), rats were treated w ith doxycycline, a matrix metalloproteinase inhibitor beginning 7 days afte r elastase perfusion. Results. AAAs consistently developed between 7 and 14 days after elastase p erfusion Aortic wall Des concentration decreased markedly during aneurysm d evelopment, reaching 3% of normal by day 14 (377 +/- 22 pmol of Des/sample on day 0 vs 9 +/- I 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 O HP/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 increase d by day 7 (P <. 05); while TE expression decreased again by day 14, PC con tinued to rise. Lysyl oxidase expression progressively decreased at all int ervals after elastase perfusion. Treatment with beta-aminoproprionitrile re sulted in acute aortic dissection in 81% of the rats (50% mortality). These early deaths occurred between days 3 and 6, coinciding with aortic infiltr ation by proteinase-secreting inflammatory cells. Delayed treatment with do xycycline 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 i s necessary to stabilize the developing aneurysm wall, it is insufficient t o prevent aneurysm progression. In contrast, reducing the proteolytic destr uction of connective tissue proteins promotes stabilization of the aneurysm al aorta.