Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model.
OBJECTIVE
Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with pre-existing atherosclerosis. We assessed the hypothesis that selective estrogen receptor modulation induces plaque stability in "menopausal" animals.


RESULTS
Atherosclerosis was induced in 42 ovariectomized New Zealand white rabbits by cholesterol feeding and mechanical injury. Animals were imaged by magnetic resonance imaging (MRI) for baseline atherosclerosis, and randomized to control (OVX (ovariectomized control group), n=12), raloxifene 35-60 mg/kg/day by diet admixture (RLX (raloxifene therapy group), n=24), or immediate sacrifice (n=6) for immunohistopathologic correlation of MRI. Six months later, rabbits underwent repeat MRI then sacrifice for micro-computed tomography (microCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2 (cyclooxygenase-2), MMP-1 (matrix metalloproteinase-1), MCP-1 (monocyte chemoattractant protein-1) expression and macrophage infiltration in RLX versus OVX with concomitant upregulation of estrogen receptor alpha (ERalpha). microCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63+/-7 degrees versus 33+/-6 degrees in OVX), the predicted result of a 53% increase in BMP-2 (bone-morphogenetic protein-2).


CONCLUSIONS
Raloxifene treatment results in reduced lesion volume, enhanced mechanical stability of vascular calcification, and less inflamed lesions characterized by less macrophage infiltration and reduced COX-2, MMP-1 and MCP-1 expression.
Choi
Brian G
BG
Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, NY, USA.
Vilahur
Gemma
G
Zafar
M Urooj
MU
Cardoso
Luis
L
Yadegar
Daniel
D
Ibanez
Borja
B
Tunstead
James
J
Viles-Gonzalez
Juan F
JF
Schaffler
Mitchell B
MB
Fuster
Valentin
V
Badimon
Juan J
JJ
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008593:Menopause; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D011817:Rabbits; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use*; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*
D018932:Chemokine CCL2; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D051546:Cyclooxygenase 2; D020781:Matrix Metalloproteinase 1