Abstract 17627: Is the Post-menopausal Rise in PCSK9 Levels Due to Loss of the Estrogen Responsive Anti-atherogenic Protein, Heat Shock Protein 27? Insights Into a Potential New PCSK9 Lowering Therapy

Abstract

Introduction: Previously we reported that elevated serum levels of Heat Shock Protein 27 represent a predictive biomarker of reduced cardiovascular clinical events. Moreover, attenuation of experimental atherogenesis, characterized by reduced cholesterol levels in both the artery wall and serum, can be achieved by augmenting serum HSP27 levels (e.g., with recombinant HSP27). PCSK9 plays a central role in regulating the abundance of hepatic LDL-receptors, and hence serum and plaque cholesterol levels. Interestingly, PCSK9 levels rise with menopause (Dallas Heart Study) and we previously published that HSP27 levels are markedly attenuated post-ovariectomy. Hence, we hypothesize that HSP27 augments hepatic cholesterol uptake via reductions in PCSK9 levels. Methods / Results: 1. In vitro studies: HepG2 (liver) cells were maintained in culture for 24 hours with or without rHSP27. The hepatic levels of apoB100 did not change with rHSP27 treatment. ApoB100 containing lipoproteins were reduced in the cell culture media with rHSP27 treatment (Western Blot: p=0.008; ELISA: p=0.0025). rHSP27 treatment reduced hepatic PCSK9 protein levels (Western Blot: p=0.019), increased LDL receptor protein levels (Western Blot: p=0.001) and increased (fluorescent) LDL uptake (p=0.022). Levels of hepatic SREBP2 and HMG-CoA reductase proteins were unaltered with rHSP27 treatment. 2. In vivo studies: Female ApoE-/- mice fed high fat diet and injected weekly with rHSP27 or PBS for 8 weeks. Serum total cholesterol and plasma PCSK9 levels were ~20-40% lower in the rHSP27 treated vs. control mice. Mice treated with rHSP27 showed reductions in aortic lesion area of ~40% for en face and ~35% for cross-sectional sinus tissue sections. Conclusions: These findings suggest that HSP27, an endogenous estrogen responsive protein, can lower extracellular cholesterol levels by reducing PCSK9 expression. Hence there is promise for the development of HSP27 “replacement” therapy for the prevention and modification of atherosclerosis via reductions in PCSK9 expression. Current clinical studies examining the relationship between HSP27 and PCSK9 levels in women undergoing prophylactic ovariectomy for BRAC1/2 (i.e., the “Angelina Effect”) are ongoing.