Heat shock protein 27–derived atheroprotection involves reverse cholesterol transport that is dependent on GM‐CSF to maintain ABCA1 and ABCG1 expression in ApoE ⁻ / ⁻ mice.

ABSTRACT Recently, we demonstrated that heat shock protein (HSP)‐27 is protective against the development of experimental atherosclerosis, reducing plaque cholesterol content by more than 30%. Moreover, elevated HSP‐27 levels are predictive of relative freedom from clinical cardiovascular events. HSP‐27 signaling occurs via the activation of NF‐kB, which induces a marked up‐regulation in expression of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF), a cytokine that is known to alter ABC transporters involved in reverse cholesterol transport (RCT). Therefore, we hypothesized that HSP‐27‐derived GM‐CSF has a potent role in impeding plaque formation by promoting macrophage RCT and sought to better characterize this pathway. Treatment of THP‐1 cells, RAW‐Blue cells, and primary macrophages with recombinant HSP‐27 resulted in NF‐kB activation via TLR‐4 and was inhibited by various pharmacologic blockers of this pathway. Moreover, HSP‐27‐induced upregulation of GM‐CSF expression was dependent on TLR‐4 signaling. Recombinant (r)HSP‐27 treatment of ApoE − / − female (but not male) mice for 4 wk yielded reductions in plaque area and cholesterol clefts of 33 and 47%, respectively, with no effect on GM‐CSF − / − ApoE − / − mice. With 12 wk of rHSP‐27 treatment, both female and male mice showed reductions in plaque burden (55 and 42%, respectively) and a 60% reduction in necrotic core area but no treatment effect in GM‐CSF − / − ApoE − / − mice. In vitro functional studies revealed that HSP‐27 enhanced the expression of ABCA1 and ABCG1, as well as facilitated cholesterol efflux in vitro by ∼10%. These novel findings establish a paradigm for HSP‐27‐mediated RCT and set the stage for the development of HSP‐27 atheroprotective therapeutics.—Pulakazhi Venu, V. K., Adijiang, A., Seibert, T., Chen, Y.‐X., Shi, C., Batulan, Z., O'Brien, E. R. Heat shock protein 27–derived atheroprotection involves reverse cholesterol transport that is dependent on GM‐CSF to maintain ABCA1 and ABCG1 expression in ApoE−/− mice. FASEB J. 31, 2364–2379 (2017). www.fasebj.org

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.