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.

Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4

“…We found that myocardial levels of TLR4 protein are increased in aging hearts. Moreover, aging hearts exhibit greater TLR4-dependent NF-κB indicate that HSP27 is also found in the extracellular space and the abundance of HSP27 in circulation is an emerging biomarker for ischemic events (47). Here we demonstrated that extracellular HSP27 is proinflammatory and detrimental, particularly in aging hearts undergoing I/R.…”

Heat Shock Protein 27 (HSP27) As a Therapeutic Target in Ischemic Stroke and Neurodegenerative Disorders

“…Thus, HSP27 overexpression has potential protective effects against cerebral ischemia and subsequent neuronal injury, implicating it as a potential therapeutic agent during stroke. Recent studies showed that extracellular HSP27 plays a role as an immunomodulator and that extracellular HSP27 is transferred intracellularly by endocytosis and directly internalization through receptors 10) . We examined HSP27 replacement therapy by injecting HSP27 intravenously, as would be done clinically, and demonstrated that intravenously injected phosphorylated HSP27 protected the brain in transient middle cerebral artery occlusion (tMCAO) model mice 25) 26) , whereby it suppressed apoptotic cell death, oxidative DNA damage, and inflammatory responses, and also preserved the blood brain barrier.…”

“…HSP27 is also found in the extracellular space where it may signal via membrane receptors to alter gene transcription and cellular function. Extracellular HSP27 is thought to be an immunomodulator 10) . HSp27 has various cytoprotective functions and is thought that overexpression or replacement of HSP27 may ameliorate pathological lesions and symptoms of or cure various diseases 1) .…”

Rac Regulates the TRAP-Induced Release of Phosphorylated-HSP27 from Human Platelets via p38 MAP Kinase but Not JNK

“…Although HSP27 exists in an unphosphorylated aggregated form, phosphorylated-HSP27 transforms into a dimer or monomer, resulting in the modulation of its chaperone activity [17,[21][22][23]. Accumulating evidence indicates that HSP27 is involved in the development of cancer, cardiovascular events and inflammatory responses in addition to its function as a molecular chaperone [21,[24][25][26]. In addition to its intracellular roles, it has recently been reported that HSP27 plays an extracellular role as a regulator of inflammation [27].…”