Extracellular Release and Signaling by Heat Shock Protein 27: Role in Modifying Vascular Inflammation

Abstract

Heat shock protein 27 (HSP27) is traditionally viewed as an intracellular chaperone protein with anti-apoptotic properties. However, recent data indicate that a number of heat shock proteins, including HSP27, are also found in the extracellular space where they may signal via membrane receptors to alter gene transcription and cellular function. Therefore, there is increasing interest in better understanding how HSP27 is released from cells, its levels and composition in the extracellular space, and the cognate cell membrane receptors involved in effecting cell signaling. In this paper, the knowledge to date, as well as some emerging paradigms about the extracellular function of HSP27 is presented. Of particular interest is the role of HSP27 in attenuating atherogenesis by modifying lipid uptake and inflammation in the plaque. Moreover, the abundance of HSP27 in serum is an emerging new biomarker for ischemic events. Finally, HSP27 replacement therapy may represent a novel therapeutic opportunity for chronic inflammatory disorders, such as atherosclerosis.

Keywords: HSPB1; atherosclerosis; coronary artery disease; extracellular HSP27; heat shock protein 27; inflammation; non-classical secretion.

Figure 1

Release of HSP27 involves non-classical secretory mechanisms. Experimental evidence suggests that HSP27 exits cells via the endolysosomal pathway and through exosomes. Localization of HSP27 to lysosomes (65) may involve the dephosphorylation of two serine residues at amino acids 15 and 82 (74); meanwhile, HSP70 appears to enter lysosomes with the aid of ABC transporters spanning the lysosomal membrane (75). Although direct protein translocation accounts for the unconventional secretion of FGF-2 (76, 77), it remains to be determined whether this mechanism plays a part in HSP27 extracellular release. Like FGF-2, HSP70 can interact with lipids as well as integrate into lipid membranes (, , –81), and it also appears that HSP70 can integrate into artificial lipid bilayers forming channels.

Figure 2

Extracellular HSP27 (eHSP27) can trigger TLR signaling, leading to NF-κB activation and cytokine upregulation (, –106).

Figure 3

Atherosclerotic plaque progression: severity of atherosclerosis correlates with increased infiltration of monocytes and their local activation into macrophages and foam cells, further promoting the inflammatory process (128, 129). HSP27 is expressed in normal areas of arteries, with reduction in expression in areas of advanced plaque (60, 61, 108, 120). Increases in HSP27 expression have also been noted in the fibrous cap and media (122).

Figure 4

Extracellular HSP27, whose release is stimulated by estrogen, affects macrophages by (i) reducing ox-LDL uptake and (ii) activating NF-κB, which results in increased secretion of IL-10 and GM-CSF (65, 103, 135).