Association of osteoprotegerin with human abdominal aortic aneurysm progression.
BACKGROUND
Abdominal aortic aneurysm (AAA) is characterized by destruction of the arterial media associated with loss of vascular smooth muscle cells, infiltration of mononuclear cells, and high concentration of metalloproteinases (MMPs) and cytokines. Osteoprotegerin (OPG) has recently been identified in atherosclerosis. The presence and functional importance of OPG in human AAA was investigated.


RESULTS
In 146 men with small AAA followed up by ultrasound for 3 years, serum OPG was weakly correlated with aneurysm growth rate. Western analysis showed 3-, 8-, and 12-fold-greater OPG concentrations in human AAA biopsies compared with biopsies of atherosclerotic narrowed aorta (1.4+/-0.1 versus 0.5+/-0.1 ng/mg tissue; P=0.002), postmortem nondiseased abdominal aorta (1.4+/-0.1 versus 0.2+/-0.1 ng/mg tissue; P<0.001), and nondiseased thoracic aorta (1.4+/-0.1 versus 0.1+/-0.06 ng/mg tissue; P<0.001). Healthy human aortic vascular smooth muscle cells incubated with recombinant human (rh)OPG (0 to 20 ng rhOPG/10(5) cells per 1 mL per 24 hours) developed an aneurysmal phenotype defined by impaired cell proliferation (P<0.001), increased apoptosis (P<0.01), and increased MMP-9 (92 kDa) expression (P<0.001). Incubation of monocytic THP-1 cells with 1 ng rhOPG/10(5) cells per 1 mL per 24 hours induced a 2-fold increase in MMP-9 expression (P<0.001), a 1.5-fold increase in MMP-2 activity (P=0.005), and a 2-fold stimulation of IL-6 production in these cells (P=0.02). Finally, secretion of OPG from human AAA explant was abrogated by treatment with the angiotensin II blocker irbesartan, with the reduction in secreted levels averaging 63.0+/-0.9 ng/mg tissue per 48-hour period.


CONCLUSIONS
These findings support a role for OPG in the growth of human AAA and suggest a potential benefit for angiotensin II blockade in slowing aneurysm expansion.
Moran
Corey S
CS
Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia.
McCann
Moira
M
Karan
Mirko
M
Norman
Paul
P
Ketheesan
Natkunam
N
Golledge
Jonathan
J
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D001012:Aorta, Abdominal / Q000166:cytology; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D017209:Apoptosis; D001706:Biopsy; D001713:Biphenyl Compounds / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D000077405:Irbesartan; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014463:Ultrasonography
D001713:Biphenyl Compounds; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; D013777:Tetrazoles; D000804:Angiotensin II; D020780:Matrix Metalloproteinase 9; D000077405:Irbesartan