Heat shock proteins (hsp) have been found to play a fundamental role in the recovery from multiple stress conditions and to offer protection from subsequent insults The function of hsp during stress goes beyond their intracellular localization and chaperone role as they have been detected outside cells activating signaling pathways Extracellular hsp are likely to act as indicators of the stress conditions, priming other cells, particularly of the immune system, to avoid the propagation of the insult Some extracellular hsp, for instance Hsp70, are associated with export vesicles, displaying a robust activation of macrophages We have coined the term Stress Observation System (SOS) for the mechanism for sensing extracellular hsp, which we propose is a form of cellular communication during stress conditions An enigmatic and still poorly understood process is the mechanism for the release of hsp, which do not contain any consensus secretory signal The export of hsp appears to be a very complex phenomenon encompassing different alternative pathways Moreover, extracellular hsp may not come in a single flavor, but rather in a variety of physical conditions This review addresses some of our current knowledge about the release and function of extracellular hsp, in particular those associated with vesicles

https://link.springer.com/content/pdf/10.1007%2Fs12192-010-0236-4.pdf

Extracellular heat shock proteins, cellular export vesicles, and the Stress Observation System: a form of communication during injury, infection, and cell damage. It is never known how far a controversial finding will go! Dedicated to Ferruccio Ritossa.

The expression of heat shock proteins (HSPs) is a basic and well-conserved cellular response to an array of stresses. These proteins are involved in the repair of cellular damage induced by the stress, which is necessary for the salutary resolution from the insult. Moreover, they confer protection from subsequent insults, which has been coined stress tolerance. Because these proteins are expressed in subcellular compartments, it was thought that their function during stress conditions was circumscribed to the intracellular environment. However, it is now well established that HSPs can also be present outside cells where they appear to display a function different than the well-understood chaperone role. Extracellular HSPs act as alert stress signals priming other cells, particularly of the immune system, to avoid the propagation of the insult and favor resolution. Because the majority of HSPs do not possess a secretory peptide signal, they are likely to be exported by a nonclassic secretory pathway. Different mechanisms have been proposed to explain the export of HSPs, including translocation across the plasma membrane and release associated with lipid vesicles, as well as the passive release after cell death by necrosis. Extracellular HSPs appear in various flavors, including membrane-bound and membrane-free forms. All of these variants of extracellular HSPs suggest that their interactions with cells may be quite diverse, both in target cell types and the activation signaling pathways. This review addresses some of our current knowledge about the release and relevance of extracellular HSPs.

/pdf/extracellular-heat-shock-proteins-a-new-location-a-new-37zvv67h7v.pdf

Extracellular heat shock proteins: a new location, a new function.

Oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases, including atherosclerosis, hypertension, heart failure, stroke and diabetes. ROS (reactive oxygen species) affect multiple tissues either directly or through NO depletion. ROS induce cardiovascular dysfunction by modulating cell contraction/dilation, migration, growth/apoptosis and extracellular matrix protein turnover, which contribute to vascular and cardiac remodelling. Of the several sources of ROS within the cardiovascular system, a family of multisubunit NADPH oxidases appears to be a predominant contributor of superoxide anion. Recent findings suggest a significant role of the genetic background in NADPH oxidase regulation. Common genetic polymorphisms within the promoter and exonic sequences of CYBA, the gene that encodes the p22(phox) subunit of NADPH oxidase, have been characterized in the context of cardiovascular diseases. This review aims to present the current state of research into these polymorphisms in their relationship to cardiovascular diseases.

NADPH oxidase CYBA polymorphisms, oxidative stress and cardiovascular diseases.

Among the oxysterols accumulating in atherosclerotic plaque, 7-ketocholesterol (7KC) is a potent apoptotic inducer, which favours myelin figure formation and polar lipid accumulation. This investigation performed on U937 cells consisted in characterizing the myelin figure formation process; determining the effects of 7KC on the PI3-K/PDK-1/Akt signalling pathway; evaluating the activities of vitamin E (Vit-E) (alpha-tocopherol) on the formation of myelin figures and the PI3-K/PDK-1/Akt signalling pathway and assessing the effects of PI3-K inhibitors (LY-294002, 3-methyladenine) on the activity of Vit-E on cell death and polar lipid accumulation. The ultrastructural and biochemical characteristics of myelin figures (multilamellar cytoplasmic inclusions rich in phospholipids and 7KC present in acidic vesicles and the reversibility of these alterations) support the hypothesis that 7KC is an inducer of phospholipidosis. This oxysterol also induces important changes in lipid content and/or organization of the cytoplasmic membrane demonstrated with merocyanine 540 and fluorescence anisotropy, a loss of PI3-K activity and dephosphorylation of PDK-1 and Akt. It is noteworthy that Vit-E was able to counteract phospholipidosis and certain apoptotic associated events (caspase activation, lysosomal degradation) to restore PI3-K activity and to prevent PDK-1 and Akt dephosphorylation. When Vit-E was associated with LY-294002 or 3-methyladenine, impairment of 7KC-induced apoptosis was inhibited, and accumulation of polar lipids was less counteracted. Thus, 7KC-induced apoptosis is a PI3-K-dependent event, and Vit-E up- and down-regulates PI3-K activity and phospholipidosis, respectively.

Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis.

Background— Although heat shock protein 60 (Hsp60) is implicated in the pathogenesis of atherosclerosis, its role in coronary heart disease (CHD) is uncertain. This study explored the influence of ...

Elevated Heat Shock Protein 60 Levels Are Associated With Higher Risk of Coronary Heart Disease in Chinese

Although immune reactions against heat shock proteins have been implicated in the pathogenesis of atherosclerosis, conflicting associations between Hsp70, anti-Hsp70 antibody and coronary heart disease (CHD) have been reported. This study assessed whether there is a significant association between extracellular human Hsp70, anti-Hsp70 antibody and acute coronary syndrome (ACS) and stable angina (SA), and examined dynamic changes in Hsp70 and anti-Hsp70 antibody levels induced by acute myocardial infarction (AMI). Plasma Hsp70 and anti-Hsp70 antibody levels in 291 patients with ACS (179 AMI, 112 unstable angina), 126 patients with SA and 417 age and sex-matched healthy subjects, and in 40 patients after admission for AMI, and on day 2, 3, and 7 after the onset of AMI were determined using enzyme-linked immunosorbent assays. Hsp70 levels were significantly higher in ACS and SA and anti-Hsp70 antibody levels were only markedly lower in ACS than controls. After adjustment for traditional CHD risk factors, increasing levels of Hsp70 were significantly associated with an increased risk and severity of ACS (P for trend < 0.001), whereas increasing levels of anti-Hsp70 antibody were associated with a decreased risk of ACS (P for trend = 0.0003). High levels of Hsp70 combined with low levels of anti-Hsp70 antibody had a joint effect on the risk of ACS (OR, 5.14, 95% CI, 3.00-8.79; P < 0.0001). In patients with AMI, Hsp70 levels decreased rapidly from days 1-7 after onset, whereas anti-Hsp70 antibody levels increased in patients with AMI. These findings suggest that higher Hsp70 levels or lower anti-Hsp70 antibody levels are independently associated with a higher risk of ACS. Higher Hsp70 levels and lower anti-Hsp70 antibody levels combine to further increase this risk.

Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome.

Associations of polymorphism of P22phox C242T, plasma levels of vitamin E, and smoking with coronary heart disease in China

Background: Several studies have suggested an association between antibody to human heat shock protein 60 (anti-Hsp60) and coronary atherosclerosis, but the results have been inconsistent. The aim of this study was to investigate the association between anti-Hsp60 and coronary heart disease (CHD) and to determine whether anti-Hsp60, hypertension, and diabetes have joint effects on CHD risk.

Methods: We measured the concentrations of anti-Hsp60 in 1003 CHD patients and 1003 age- and sex-matched control subjects without CHD events.

Results: Concentrations of anti-Hsp60 were significantly higher in CHD patients than in controls. Increasing concentrations of anti-Hsp60 were significantly associated with higher risk of CHD ( P for trend <0.0001) and with increasing severity of CHD as assessed by number of diseased vessels detected with angiography [odds ratio (OR) 3.67, 95% CI 1.56–8.64, P = 0.003] after multivariate adjustment for traditional CHD risk factors. There were strong joint effects of high concentrations of anti-Hsp60 and hypertension (OR 5.17, 95% CI 3.95–6.75, P < 0.0001) and diabetes (OR 6.49, 95% CI 4.52–9.33, P < 0.0001) on CHD risk; simultaneous occurrence of high anti-Hsp60 concentrations, hypertension, and diabetes conferred a dramatically higher risk of CHD (OR 20.99, 95% CI 12.50–35.24, P < 0.0001) in multivariate analyses.

Conclusions: Anti-Hsp60 is independently associated with CHD risk, and a combination of high anti-Hsp60, hypertension, and diabetes is particularly detrimental for CHD risk.

Joint Effects of Antibody to Heat Shock Protein 60, Hypertension, and Diabetes on Risk of Coronary Heart Disease in Chinese

High levels of circulating heat shock protein 60 (Hsp60) and antibody to human Hsp60 have been associated with greater risk of coronary heart disease (CHD) in several studies, but associations between polymorphisms of the hsp60 gene and CHD risk have not been investigated. By resequencing DNA from 30 unrelated Han Chinese and using HapMap Phase I Chinese data of hsp60 gene, we selected four tagging single nucleotide polymorphisms (tagSNPs) named rs2340690, rs788016, rs2305560, and rs2565163, and determined their frequencies in 1,003 Chinese CHD patients and 1,003 age- and sex-frequency-matched controls. Furthermore, we used PHASE 2.0 software to reconstruct haplotypes and logistic regression to control for potential confounders in multivariate analyses. We found 13 SNPs in hsp60 gene (including four novel SNPs) in Han Chinese subjects. Our results showed no significant differences in four selected SNPs in patients with CHD and controls after adjusting for other conventional risk factors and stratifying by age, sex, smoking status, past history of hypertension and DM; however, our results showed that subjects with the GCTC haplotype had about twofold higher risk of CHD than those with the GTTC haplotype (OR = 1.91, 95%CI: 1.26–2.89, P = 0.002). Our results suggest that the GCTC haplotype in the hsp60 gene is significantly associated with higher CHD risk in a Chinese population.

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Ying Chen

Papers

Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome.

Associations of polymorphism of P22phox C242T, plasma levels of vitamin E, and smoking with coronary heart disease in China

Joint Effects of Antibody to Heat Shock Protein 60, Hypertension, and Diabetes on Risk of Coronary Heart Disease in Chinese

Genetic variation in heat shock protein 60 gene and coronary heart disease in China: tagging-SNP haplotype analysis in a case-control study