Downregulation of remodelling enzymatic activity induced by an angiotensin-converting enzyme inhibitor (perindopril) reduces the degeneration of experimental abdominal aortic aneurysms in a rat model.
OBJECTIVE
Angiotensin-converting enzyme (ACE) inhibitors have proven their ability to affect vascular wall remodelling, in addition to their anti-hypertensive effects. The aim of this study was to assess the impact of perindopril on the development of abdominal aortic aneurysm (AAA) in a rat model, and its correlation to enzyme activities involved in vascular wall remodelling.


METHODS
The model of the decellularised aortic xenograft in Lewis rat was chosen. Rats were randomised to two groups: group P fed with 3 mg kg(-1) of perindopril daily during 30 days, or control group C (n = 15 per group)). Rats were euthanised at 30 days for analysis. AAA growth and histological changes in the aortic wall were measured by histomorphometry. Proteolytic activities were measured by gelatin zymography of conditioned medium for activematrix metalloproteinase 9/pro-matrix metalloproteinase 9 (MMP9/pro-MMP9) and activeMMP2/pro-MMP2, and by quantitative immunofluorescence tissue for elastase and plasmin.


RESULTS
The mean maximal diameter of AAAs at 30 days was significantly lower in the treated group P compared with the control group C (2.5 ± 1.0 vs. 4.9 ± 2.1 mm; P < 0.01). The expansion rate of AAAs after 30 days was significantly reduced in group P compared with group C (36 ± 14% vs. 67 ± 23%; P < 0.01). Pro-MMP9 and MMP9 activities were significantly decreased in relative intensity (RI) in group P compared with group C (0.43 ± 0.64 RI vs. 1.02 ± 0.61 RI, P = 0.01; 0.18 ± 0.57 RI vs. 0.66 ± 1.19 RI, P = 0.004). The activation rate of MMP2 was also significantly lower in group P compared with group C (1.27 ± 0.42 vs. 1.67 ± 0.44; P = 0.002). Elastase and plasmin tissue activities were significantly lower in group P compared with group C, respectively (3.9 ± 3.3 vs. 5.8 ± 3.7 IF min(-1) g(-1),and 25.9 ± 23.9 vs. 49.1 ± 38.7 IF min(-1) g(-1); P < 0.05).


CONCLUSIONS
After 30 days of treatment by perindopril, a significant decrease in aneurysmal degeneration of the decellularised aortic xenograft AAA model was observed. This phenomenon appears to be induced by a downregulation of enzymes involved in the aortic wall remodelling during aneurysmal degeneration.
Service de Chirurgie Cardiaque et Vasculaire, Hôpital Européen Georges Pompidou, APHP, Université René Descartes, Faculté de Médecine, Paris 5, France. jean-marc.alsac@egp.aphp.fr
J-M
JM
Alsac
C
C
Journe
L
L
Louedec
J
J
Dai
P
P
Julia
J-N
JN
Fabiani
J-B
JB
Michel
D000803:Angiotensin I / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D001019:Aortic Rupture / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006168:Guinea Pigs; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D020913:Perindopril / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012083:Renin / Q000097:blood; D013997:Time Factors; D014183:Transplantation, Heterologous
D000806:Angiotensin-Converting Enzyme Inhibitors; D004792:Enzyme Precursors; D000803:Angiotensin I; D010447:Peptide Hydrolases; D010196:Pancreatic Elastase; D005341:Fibrinolysin; D012083:Renin; D018093:Gelatinases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D020913:Perindopril