Extracellular Release of the Atheroprotective Heat Shock Protein 27 Is Mediated by Estrogen and Competitively Inhibits acLDL Binding to Scavenger Receptor-A

Abstract

Abstract-We recently identified heat shock protein 27 (HSP27) as an estrogen receptor beta (ER␤)-associated protein and noted its role as a biomarker for atherosclerosis. The current study tests the hypothesis that HSP27 is protective against the development of atherosclerosis. HSP27 overexpressing (HSP27 o/e ) mice were crossed to apoE Ϫ/Ϫ mice that develop atherosclerosis when fed a high-fat diet. Aortic en face analysis demonstrated a 35% reduction (PՅ0.001) in atherosclerotic lesion area in apoE Ϫ/Ϫ HSP27 o/e mice compared to apoE Ϫ/Ϫ mice, but primarily in females. Serum HSP27 levels were Ͼ10-fold higher in female apoE Ϫ/Ϫ HSP27 o/e mice compared to males, and there was a remarkable inverse correlation between circulating HSP27 levels and lesion area in both male and female mice (r 2 ϭ0.78, PՅ0.001). Mechanistic in vitro studies showed upregulated HSP27 expression and secretion in macrophages treated with estrogen or acLDL. Moreover, exogenous HSP27 added to culture media inhibited macrophage acLDL uptake and competed for the scavenger receptor A (SR-A)-an effect that was abolished with the SR-A competitive ligand fucoidan and absent in macrophages from SR-A Ϫ/Ϫ mice. Furthermore, extracellular HSP27 decreased acLDL-induced release of the proinflammatory cytokine IL-1␤ and increased the release of the antiinflammatory cytokine IL-10. HSP27 is atheroprotective, perhaps because of its ability to compete for the uptake of atherogenic lipids or attenuate inflammation.

Small heat shock proteins in ageing and age-related diseases

“…The potential role of HSPB1 in CVD originated from studies of human vascular tissue. HSPB1 secretion decreases in atherosclerotic plaques, compared to healthy tissues, and soluble HSPB1 plasma levels also decline in atherosclerotic patients compared to healthy subjects (Martin-Ventura et al 2004), whereas overexpression of HSBP1 in atherosclerotic mouse models ameliorates foam cell formation and reduces atherosclerotic plaque area (Rayner et al 2008). These findings suggest a protective role for sHSPs in atherogenesis, however, the precise mechanisms of action remain obscure, largely due to the diverse nature of each sHSP family member.…”

“…Lower circulating HSPB1 serum levels were documented in atherosclerotic coronary arteries and were inversely associated with increasing plaque progression and age. Thus, serum release of HSPB1 seems to have an atheroprotective and potentially an anti-ageing role (Batulan et al 2016;Kardys et al 2008;Lepedda et al 2009;Martin-Ventura et al 2004;Miller et al 2005;Rayner et al 2008). In a mouse model of atherosclerosis, exogenous administration of HSPB1 reduced plaque progression, corroborating its atheroprotective properties and further suggesting a potential therapeutic benefit ).…”

“…The association with circulating oestrogen levels further suggests sex-related effects of HSPB1. Indeed, the atheroprotective effects of HSPB1 were more pronounced in female mouse models (Rayner et al 2008). Since, atherosclerosis is primarily a chronic inflammatory disease, the link between secreted sHSPs and the immune system was soon appraised.…”

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

“…It is therefore hypothesised that HSP27 is atheroprotective because of its actions on the macrophage population either or both competing for the uptake of atherogenic lipids or attenuating inflammation. (Rayner et al 2008). …”

Thymosin Beta‐4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction

“…Another correlate, NF‐kappa‐B essential modulator, is an X‐linked gene that is cardioprotective in experimental HF through NF‐κB‐mediated modulation of oxidative stress 43. HSP27 is also cardioprotective and activates the NF‐κB pathway44, 45; its secretion is regulated by estrogen46 and shows elevated expression levels in HFpEF 47. Epidermal growth factor and Src are both part of the extranuclear estrogen signaling network,48 can also activate the NF‐κB pathway,49 and play a role in both vascular and immune processes 50.…”