Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

Shi, Chunhua; Ulke‐Lemée, Annegret; Deng, Jingjing; Batulan, Zarah; O’Brien, Edward R.

doi:10.1096/fj.201800987r

Cited by 57 publications

(48 citation statements)

References 37 publications

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“…For example, in the large Anglo-Scandinavian Cardiac 2 Outcome Trial (ASCOT), elevated levels of IgG (regardless of the recognized antigen) are 3 associated with a reduced risk of coronary heart disease 32 . While we also observed increased 4 IgM levels, unlike IgG AAb they did not independently associate with either health or CVD. 5 Currently, we are exploring how these IgG AAbs facilitate HSP27 signaling, interacting with 6 TLR4 to bind at the cell surface and activate NF-kB.…”

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confidence: 66%

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Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

Chen

Shi

Deng

et al. 2020

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1Elevated Heat Shock Protein 27 levels predict relative freedom from cardiovascular events. In 2 ApoE -/mice HSP27 over-expression or twice daily subcutaneous injections reduce blood and 3 plaque cholesterol levels, inflammation and atherogenesis. While natural antibodies to HSP27 4 are present in human blood their role is unknown. Here, we show that blood levels of both 5 HSP27 and anti-HSP27 IgG antibodies are elevated in healthy controls compared to patients with 6 cardiovascular disease. ApoE -/mice vaccinated with recombinant HSP25 (murine ortholog) 7 develop elevated anti-HSP25 IgG antibodies and reduced levels of cholesterol, inflammation and 8 atherosclerosis. The effects on cholesterol metabolism were divergent: increased hepatic LDLR 9 expression and reduced plasma PCSK9 levels. In vitro, a polyclonal anti-HSP27 IgG antibody 10 combined with rHSP27 to upregulate hepatocyte LDLR expression via an NF-kB-dependent 11 pathway that is independent of SREBP2 expression and intracellular cholesterol levels. HSP27 12 immunotherapy represents a novel means of lowering not only cholesterol but also PCSK9. 13Small heat shock proteins, such as Heat Shock Protein 27 (HSP27), are intracellular chaperones 1 that promote the proper reassembly of misfolded proteins and act as mediators of extracellular 2 cellular signaling 1 . HSP27 effectively preserves cellular homeostasis under various conditions of 3 degenerative or inflammatory stress -including those common to the pathogenesis of 4 atherosclerosis 2 . There is overwhelming genetic, epidemiological and clinical evidence that 5 irrefutably establishes low density lipoprotein cholesterol (LDL-C) as causal for atherosclerosis 3, 6 4 . Experiments from our group 5 and four others using proteomic discovery approaches 6,7,8,9 show 7 that serum HSP27 levels decline as human atherosclerosis develops, with its tissue abundance 8 inversely corelated with the degree of coronary artery plaque burden. In atherosclerosis-prone 9 Apolipoprotein E null (ApoE -/-) mice augmentation of extracellular HSP27 levels via constitutive 10 over-expression, transplantation of bone marrow from mice that over-express HSP27, twice-11 daily subcutaneous administration of recombinant HSP27 (rHSP27; 100 µg) or estrogenic 12 therapy post-ovariectomy (that augment HSP27 blood levels) reduce both plasma and plaque 13 cholesterol content, resulting in the formation of more stable plaques that are less inflamed 10, 11, 14 12, 13 . Clinically, elevated HSP27 blood levels are associated with a lower 5-year risk of 15 myocardial infarction, stroke or cardiovascular death 11 . Interestingly, natural antibodies to 16 HSP27 (AAbs) are detectable in the blood, yet their biological significance is unclear 14, 15 . 18In this study we sought to address three questions. First, what is the correlation between blood 19 HSP27 and AAb abundance in human cardiovascular disease (CVD) patients compared to 20 healthy control subjects (CON)? Second, does augmenting levels of antibodies to HSP25 (the 21 murine ortholog of ...

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confidence: 66%

“…5A) SREBP2 protein 2 expression remained unchanged with rHSP25 vaccination and [rHSP27 + PAb] treatments. 3 Indeed, this increase in HepG2 LDLR expression occurred without a reduction in intracellular 4 cholesterol concentration. Treatment with [rHSP27 + PAb] produced an increase in LDL-C 5 uptake and intra-cellular cholesterol concentration (Fig.…”

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confidence: 88%

Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

Chen

Shi

Deng

et al. 2020

Preprint

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“…An immediate responses to stress, inflammation, and cellular damage is to secrete HSP27 into the blood to protect the body [20]. Given the protective role of HSP27 in protecting vessels from oxidative stress [21] and inhibiting inflammation [22], the higher levels of serum HSP27 observed in the IMT (+) group compared with the IMT (-) group in our study may represent a consequence of a compensatory response to inflammation and oxidative stress in the early stage of atherosclerosis. HSP27 may have been induced to counteract these unfavorable factors in the initiation of atherosclerosis.…”

Section: Discussionmentioning

confidence: 63%

Circulating heat shock protein 27 as a novel marker of subclinical atherosclerosis in type 2 diabetes: a cross-sectional community-based study

Wang

Shi

Lü

et al. 2020

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Background Heat shock protein 27 (HSP27) has been proposed as a vital protective factor in atherosclerosis. The objective of the present study was to evaluate the association between circulating HSP27 and intima-media thickness (IMT) of the common carotid artery in individuals with type 2 diabetes and to determine whether HSP27 represents an independent marker for subclinical atherosclerosis in this patient population.Methods We performed a cross-sectional community-based study consisting in 186 Chinese subjects with a median duration of diabetes of 8.2 years who underwent carotid ultrasound IMT measurement.Serum HSP27 levels were assessed by ELISA.Results Serum HSP27 levels were significantly higher in the IMT (+, >1.0 mm) group than in the IMT (-, ≤1.0 mm) group, with the median value of 8.80 ng/mL (5.62-12.25) and 6.93 ng/mL (4.23-9.60), respectively ( P =0.006). The discriminative value of HSP27 to evaluate IMT was 7.16 ng/mL and the area under the curve was 0.72 (95%CI=0.64-0.80, P=0.0065). Spearman's rank correlation analysis demonstrated that the concentrations of circulating HSP27 were positively correlated with carotid IMT ( r =0.198, P =0.007) and blood urea nitrogen ( r =0.170, P <0.05). Furthermore, in the logistic model, serum HSP27 levels were found to be independent predictors of carotid IMT in type 2 diabetic patients after adjustment for onset age of diabetes, blood pressure, total cholesterol and C-reactive protein. (OR=1.085, P =0.022).Conclusions Circulating HSP27 level positively correlates with carotid IMT, is an independent predictor for early atherosclerotic changes in diabetes, and may represent a novel marker of subclinical atherosclerosis in type 2 diabetes.

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“…EVs are often important for animals and humans, especially when afflicted by infectious diseases. It appears, therefore, that the EV cocktails from the blood or other origin can induce apparently opposite effects, programmed towards pro-or antiinflammatory cell phenotypes [23,[27][28][29][30][31][32]. The EVs most effective for intervention in the latter responses are those derived from mesenchymal stromal cells (MSCs) [26].…”

Section: Immune Cell Diseasesmentioning

confidence: 99%

“…However, effects induced by miscellaneous EVs have also been of antiinflammatory type. It appears, therefore, that the EV cocktails from the blood or other origin can induce apparently opposite effects, programmed towards pro-or antiinflammatory cell phenotypes [23,[27][28][29][30][31][32].…”

Section: Immune Cell Diseasesmentioning

confidence: 99%

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

Meldolesi

2019

Clinical and Experimental Immunology

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Two types of extracellular vesicles (EVs), exosomes and ectosomes, are generated and released by all cells, including immune cells. The two EVs appear different in many properties: size, mechanism and site of assembly, composition of their membranes and luminal cargoes, sites and processes of release. In functional terms, however, these differences are minor. Moreover, their binding to and effects on target cells appear similar, thus the two types are considered distinct only in a few cases, otherwise they are presented together as EVs. The EV physiology of the various immune cells differs as expected from their differential properties. Some properties, however, are common: EV release, taking place already at rest, is greatly increased upon cell stimulation; extracellular navigation occurs adjacent and at distance from the releasing cells; binding to and uptake by target cells are specific. EVs received from other immune or distinct cells govern many functions in target cells. Immune diseases in which EVs play multiple, often opposite (aggression and protection) effects, are numerous; inflammatory diseases; pathologies of various tissues; and brain diseases, such as multiple sclerosis. EVs also have effects on interactive immune and cancer cells. These effects are often distinct, promoting cytotoxicity or proliferation, the latter together with metastasis and angiogenesis. Diagnoses depend on the identification of EV biomarkers; therapies on various mechanisms such as (1) removal of aggression-inducing EVs; (2) EV manipulations specific for single targets, with insertion of surface peptides or luminal miRNAs; and (3) removal or re-expression of molecules from target cells.

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Characterization of heat shock protein 27 in extracellular vesicles: a potential anti‐inflammatory therapy

Cited by 57 publications

References 37 publications

Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

Circulating heat shock protein 27 as a novel marker of subclinical atherosclerosis in type 2 diabetes: a cross-sectional community-based study

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

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