Abstract 520: Chronic Overexpression of Heat Shock Protein 27 Facilitates Favorable Plaque Remodeling?

Abstract

Background: Previously, we discovered that over-expression of Heat Shock Protein 27 (HSP27) in atherosclerosis-prone apoE -/- mice (apoE -/- HSP27 o/e ) maintained on a high fat diet (HFD) for 4 weeks reduces aortic lesion area - however, only in females. Purpose/Objective: To determine if chronic HSP27 over-expression modulates plaque lesion characteristics including aortic mechanical properties. Methods/Results: Male and female apoE -/- and apoE -/- HSP27 o/e mice fed a high fat diet for 12 weeks were studied. Relative to apoE -/- mice, female apoE -/- HSP27 o/e mice had aortic lesion area reductions of 35% for en face and 30% for cross-sectional sinus tissue sections. Interestingly, the same parameters were also reduced by 21% and 24%, respectively, in male cohorts. Aortic plaques from apoE -/- HSP27 o/e mice showed almost 50% reductions in the area occupied by cholesterol clefts and free cholesterol, with fewer macrophages and reduced macrophage apoptosis. The mechanical properties of the aorta were studied ex vivo using 2-mm vessel segments (n=14-20/group). We developed an apparatus to determine vessel stiffness during radial stretching at a constant rate, recording tension via a force transducer. There was an increase in vessel stiffness in apoE -/- HSP27 o/e mice compare to apoE -/- (female: 628±30Pa vs 444±38Pa, p<0.001; male: 679±19Pa vs 505±22Pa; p<0.001). The vasoactive response of aortic segments (n=12/group) to phenylephrine (PE), carbachol (CCh) and sodium nitroprusside (SNP) were also determined. While the vasorelaxation response induced by CCh and SNP were similar between the two animal groups, PE (10μM) produced a greater increase in vasoconstriction in apoE -/- HSP27 o/e mice compared to apoE -/- (female: 205±9% vs 162±10%, p<0.001; male: 190±9% vs 139±12%, p<0.01). Conclusion: Chronic over-expression of HSP27 provides a persistent atheroprotective effect that benefits both sexes and coincides with remarkable reductions in lesion cholesterol accumulation as well as macrophage apoptosis. In addition, it increases the aortic stiffness and the vasoactive response to PE in apoE -/- mice model. These data provide new clues as to how HSP27 may improve atherosclerotic lesion stability.