Abstract 1948: Over-expression of HSP27 Provides Chronic Atheroprotection: Reductions in Foam Cell Content and Inflammatory Responses

Abstract

Introduction: Heat Shock Protein 27 (HSP27) was recently shown by our laboratory to be a biomarker of atherosclerosis and after 4 weeks of a high fat diet (HFD) apoE −/− mice that over-express HSP27 (or apoE −/− HSP27 o/e mice) show a marked attenuation of aortic lesion size compared to apoE −/− mice - but only in females (ATVB 20005; Circ Res in press). Moreover, we demonstrated that serum HSP27 levels were inversely related to atherosclerotic burden, estrogens mediated the release of HSP27 from cells and extracellular HSP27 bound to Scavenger Receptor-A where it could competitively inhibit acLDL uptake. Purpose/Methods: The goal of this study was to determine if and how HSP27 over-expression persistently attenuates atherogenesis in apoE −/− mice fed a HFD for 12 weeks. Results: Compared to female apoE −/− mice, female apoE −/− HSP27 o/e mice showed persistent reductions in aortic (en face) lesion area and aortic sinus cross-sectional lesion area at 12 weeks (e.g., 38% and 39% respectively vs. 35% and 40% after 4 weeks of HFD). Although our original studies revealed that male apoE −/− HSP27 o/e mice had no protection from atherogenesis after 4 weeks of a HFD, in the current study we noted that 12 weeks of a HFD resulted in a 17% reduction in aortic (en face) lesion area and a 24% attenuation in aortic sinus cross-sectional lesion area with HSP27 over-expression. While lesions observed after 4 weeks of HFD consisted mainly of lipid-laden foam macrophages, after 12 weeks of HFD the histopathology was different and included a distinct foam cell layer (or FCL) luminal to a deeper necrotic layer (e.g., with cholesterol crystals). The FCL area was reduced in size in apoE −/− HSP27 o/e vs. apoE −/− mice (e.g., −63% in females, p=0.03; and −48% in males, p=0.02). In vitro, macrophages from apoE −/− HSP27 o/e mice showed a reduction in TNF-α expression compared to apoE −/− mice (e.g., 40% at baseline, and 55% after LPS provocation). Conclusions: Over-expression of HSP27 provides a persistent atheroprotective effect that benefits both sexes. Chronic lesions are not only smaller in size with HSP27 over-expression but show fewer foam cells and macrophages are less pro-inflammatory. These results highlight a potential clinical role for chronic HSP27 modulation for atheroprotection.