title: Selective estrogen receptor modulation influences atherosclerotic plaque composition in a rabbit menopause model.
abstract: 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.
authors: Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, NY, USA.
authors: Brian G
authors: BG
authors: Choi
authors: Gemma
authors: G
authors: Vilahur
authors: M Urooj
authors: MU
authors: Zafar
authors: Luis
authors: L
authors: Cardoso
authors: Daniel
authors: D
authors: Yadegar
authors: Borja
authors: B
authors: Ibanez
authors: James
authors: J
authors: Tunstead
authors: Juan F
authors: JF
authors: Viles-Gonzalez
authors: Mitchell B
authors: MB
authors: Schaffler
authors: Valentin
authors: V
authors: Fuster
authors: Juan J
authors: JJ
authors: Badimon
mesh_terms: 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*
chemical_list: D018932:Chemokine CCL2; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D051546:Cyclooxygenase 2; D020781:Matrix Metalloproteinase 1