title: 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 occursviathe activation of NF-κB, 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-κB activationviaTLR-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 vitrofunctional studies revealed that HSP-27 enhanced the expression of ABCA1 and ABCG1, as well as facilitated cholesterol effluxin vitroby ∼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.
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Vivek Krishna
authors.initials: VK
authors.lastname: Pulakazhi Venu
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ayinuer
authors.initials: A
authors.lastname: Adijiang
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Seibert
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Chen
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Zarah
authors.initials: Z
authors.lastname: Batulan
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada ermobrie@ucalgary.ca.
authors.forename: Edward R
authors.initials: ER
authors.lastname: O'Brien
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001057:Apolipoproteins E; D002784:Cholesterol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D055551:HSP27 Heat-Shock Proteins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse
keywords: NF-κB; Toll-like receptors; atherosclerosis; macrophages