Abstract 15504: Heat Shock Protein 27 Mediated Atheroprotetion Requires Scavenger Receptor-A: Mechanistic Insight Into a Novel Therapeutic
Introduction: Scavenger Receptor-A (SR-A) plays a central role in foam cell formation and atherogenesis. Previously, we demonstrated that heat shock protein (HSP)-27 attenuates atherogenesis in ApoE-/- mice and interacts with SR-A; yet the precise mechanism of atheroprotection remained elusive.
Purpose: We set out to ascertain the mechanism by which recombinant (r)HSP27 attenuates foam cell formation and determine the role of SR-A in HSP27 mediated atheroprotection.
Methods/Results: Initially we sought to determine if HSP27 activates the nuclear factor-kappa B (NF-kB), a master regulator of many atherosclerosis-related gene programs. Indeed, rHSP27 activated NF-kB signaling in a THP1 reporter assay. Moreover, bone marrow derived mouse or THP1 human macrophages treated with rHSP27 blocked uptake (38% reduction, p<0.05) and binding of acLDL (34% reduction; p<0.005). We next examined the effect of HSP27 on SR-A levels and noted a 40% (p<0.05) reduction in mRNA (Q-PCR) and a reduction in SR-A protein levels as assayed by Western blot and Flow Cytometry (60% and 15% reduction respectively, p<0.05). Notably, pharmacologic inhibition of NF-KB signaling (BAY compound) attenuated the effects of rHSP27, restoring SR-A expression and concomitant lipid uptake. Finally, to determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE-/-SR-A-/- mice fed a high fat diet were injected subcutaneously with rHSP25 (mouse homologue of HSP27) or vehicle control for 3 weeks. While rHSP25 reduced en face aortic atherosclerotic lesion size by 50% in ApoE-/- mice, the effect was completely abrogated in ApoE-/-SR-A-/- mice.
Conclusion: rHSP27 transcriptionally down regulates SR-A expression via a NF-kB dependent mechanism. Furthermore, reductions in atherosclerotic burden by rHSP27 require SR-A, providing insight into the mechanism by which HSP27 mediates it's biological effect.
- © 2011 by American Heart Association, Inc.