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. Methods and 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 (μCT) 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 α (ERα). μCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63 ± 7° versus 33 ± 6° 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.