Abstract 5460 Heat Shock Protein 27 Over-Expression in Hematopoietic Cells is Atheroprotective and Anti-Inflammatory

Abstract

Previously, we demonstrated that Heat shock protein 27 (HSP27) shows diminished expression with progression of human coronary atherosclerosis [ATVB 2005]. Moreover, we have shown that global over-expression of HSP27 (HSP27 o/e ) protects against the development of atherosclerosis in ApoE −/− mice in part via binding to Scavenger Receptor-A [Circ Res 2008]. More recent experiments reveal that macrophage apoptosis is less frequent in advanced (12 wk) lesions from apoE −/− HSP27 o/e mice and highlight macrophage specific anti-inflammatory protective mechanisms. The purpose of this study was to determine if blood-borne cells (e.g., mononuclear cells) are sufficient and required for the HSP27 atheroprotective phenotype in female ApoE −/− mice. Methods/Results: Female ApoE −/− mice (~10 Weeks old and ≥ 18.5 g), underwent μ -irradiation to eliminate endogenous bone marrow before receiving bone marrow from either female ApoE −/− or ApoE −/− HSP27 o/e donors. After 6 weeks of recovery recipients were placed on a high fat/cholesterol diet for 4 weeks to induce atherosclerosis before being euthanized. ApoE −/− mice receiving bone marrow from ApoE −/− HSP27 o/e had detectable levels of HSP27 mRNA in liver and spleen. In addition, the HA tag of the over-expression construct was detectable in liver sections and HSP27 was measured in the serum from mice receiving the ApoE −/− HSP27 o/e bone marrow. Over-expression of HSP27 in cells of hematopoietic origin resulted in a 52% reduction in aortic en face lesion burden (p=0.005) and a 32% reduction in the lesion area found in aortic sinus cross-sections (p=0.02). The macrophage content of lesions in both murine populations was similar. In vitro bone marrow derived macrophages from ApoE −/− HSP27 o/e mice had a 2.7-fold decrease in oxidized LDL uptake after 24 hrs (p=0.002) and were less adherent to LPS activated HUVECs (p<0.05) when compared to ApoE −/− derived macrophages. In conclusion, the over-expression of HSP27 in bone marrow derived cells is sufficient and necessary to provide atheroprotection in ApoE −/− mice and points to a central role for HSP27 in reducing the inflammatory milieu of atherosclerotic lesions.