Abstract 472: Overexpression of the estrogen receptor beta associated protein, Heat Shock Protein 27, is Sex Specific and Atheroprotective
Introduction: We discovered that Heat Shock Protein 27 (HSP27) is an estrogen receptor associated protein that represses estrogen mediated transcription (ATVB 2005) and shows decreased expression in human coronary arteries as the stage of coronary atherosclerosis progresses. Moreover, we note that serum levels are >3-fold higher in normal controls compared to patients with stable CAD.
Purpose/Methods: To determine if HSP27 is protective against the development of atherosclerosis we compared lesion development in atherosclerosis-prone apoE−/− mice vs. apoE−/− mice that over-expressed human HSP27 (hHSP27apoE−/−). All mice were fed a cholesterol supplemented diet for 4 weeks before being euthanized at age 10 weeks.
Results: All mice were viable, free of phenotypic anomalies and had similar cholesterol levels (approx. 1100 mg/dL). There was a 41% reduction in (en face) aortic lesion area and a decrease in vessel wall lipid deposition/inflammation in female hHSP27apoE−/− vs. apoE−/− mice (p<0.001). Interestingly, male mice failed to show these reductions. Serum hHSP27 levels were undetectable when mice were fed a normal diet, but with 4 weeks of a cholesterol enriched diet rose 10-fold in female hHSP27apoE−/− mice (281±154 vs. 2770±858 pg/ml; ANOVA p≤0.02), yet remained low and relatively constant in their male littermates. There was an impressive negative correlation between serum hHSP27 levels and atherosclerotic lesion burden in female mice (R2=0.902, p<0.001). In vitro, macrophages from hHSP27apoE−/− mice showed a 30% reduction in cell migration (p≤0.01) and a 53% reduction in cell attachment to collagen (p<0.001).
Conclusions: Over-expression of HSP27 is sex specific and serum levels correlate inversely with atherogenic burden. HSP27 attenuated macrophage adhesion and migration, and its over-expression was associated with reduced lesion lipid accumulation/inflammation - observations that fit well with our separately submitted data on the interplay between HSP27 and cholesterol uptake.