Heat shock protein 72 in heart failure

In the heart, Heat Shock Proteins (HSP) constitute an endogenous stress response that protect myocytes from damage. Although HSP are intracellular proteins, these can be found also in peripheral circulationwhere their increase is associated with early cardiovascular disease

Bacterial Infection Elicits Heat Shock Protein 72 Release from Pleural Mesothelial Cells

Heat shock protein 70 (HSP70) has been implicated in infection-related processes and has been found in body fluids during infection. This study aimed to determine whether pleural mesothelial cells release HSP70 in response to bacterial infection in vitro and in mouse models of serosal infection. In addition, the in vitro cytokine effects of the HSP70 isoform, Hsp72, on mesothelial cells were examined. Further, Hsp72 was measured in human pleural effusions and levels compared between non-infectious and infectious patients to determine the diagnostic accuracy of pleural fluid Hsp72 compared to traditional pleural fluid parameters. We showed that mesothelial release of Hsp72 was significantly raised when cells were treated with live and heat-killed Streptococcus pneumoniae. In mice, intraperitoneal injection of S. pneumoniae stimulated a 2-fold increase in Hsp72 levels in peritoneal lavage (p<0.01). Extracellular Hsp72 did not induce or inhibit mediator release from cultured mesothelial cells. Hsp72 levels were significantly higher in effusions of infectious origin compared to non-infectious effusions (p<0.05). The data establish that pleural mesothelial cells can release Hsp72 in response to bacterial infection and levels are raised in infectious pleural effusions. The biological role of HSP70 in pleural infection warrants exploration

Heat Shock Protein 72 Regulation of Metabolism

The prevalence of metabolic disease continues to rise in the United States, leading to conditions such as metabolic syndrome, diabetes, and NAFLD. Heat shock proteins (HSPs) are molecular chaperones which aid in protein folding during cellular stress. These proteins are also important in metabolic function, through inhibiting inflammation and increasing oxidative capacity in skeletal muscle. Reduced HSPs may also lead to metabolic disease, demonstrated by reduced HSP72 expression in skeletal muscle of diabetic patients and in the liver with the progression of NAFLD. Our studies further demonstrate that disruption in the HSP response could be an underlying commonality in various metabolic conditions and tissues. First, we found that a reduction in HSPs in skeletal muscle of a post-menopausal rat model is associated with reduced mitochondrial protein expression, increased lipid storage, and reduced exercise capacity. We also investigated the role of HSP72 in the liver. A loss of HSP72 in hepatocytes led to a reduction in fatty acid oxidation, mitochondrial dysfunction, and increased lipid storage. A reduction in HSPs in both the skeletal muscle and the liver may increase susceptibility to the development of metabolic disease. Our work also demonstrates that activation of HSPs has potential to protect from metabolic dysfunction. We found that a heat treatment intervention increases HSP72 in the liver, reduces hepatic triglyceride storage, and improves whole-body glucose homeostasis in rodents fed a high-fat diet. We also found that acute and chronic exercise increase HSP72 protein expression in the liver. The induction of HSPs with exercise was associated with changes in autophagy and mitophagy protein expression, which may protect hepatocytes from accumulation of damaged organelles. This work strongly suggests that HSP72 maintains whole-body metabolic homeostasis through protecting against lipid accumulation in both skeletal muscle and liver. Therapies which activate HSP72 may be the key to protecting against metabolic disease

Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children

Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes

Bacterial infection elicits heat shock protein 72 release from pleural mesothelial cells

Heat shock protein 70 (HSP70) has been implicated in infection-related processes and has been found in body fluids during infection. This study aimed to determine whether pleural mesothelial cells release HSP70 in response to bacterial infection in vitro and in mouse models of serosal infection. In addition, the in vitro cytokine effects of the HSP70 isoform, Hsp72, on mesothelial cells were examined. Further, Hsp72 was measured in human pleural effusions and levels compared between non-infectious and infectious patients to determine the diagnostic accuracy of pleural fluid Hsp72 compared to traditional pleural fluid parameters. We showed that mesothelial release of Hsp72 was significantly raised when cells were treated with live and heat-killed Streptococcus pneumoniae. In mice, intraperitoneal injection of S. pneumoniae stimulated a 2-fold increase in Hsp72 levels in peritoneal lavage (p,0.01). Extracellular Hsp72 did not induce or inhibit mediator release from cultured mesothelial cells. Hsp72 levels were significantly higher in effusions of infectious origin compared to non-infectious effusions (p,0.05). The data establish that pleural mesothelial cells can release Hsp72 in response to bacterial infection and levels are raised in infectious pleural effusions. The biological role of HSP70 in pleural infection warrants exploration

The effectiveness of HS-72 variants in inhibition of heat shock protein 72

Heat shock proteins (HSPs) play important roles in the process of maintaining proteostasis in a cell. HSP72, the inducible form of the HSP70 family, is expressed in response to stress on the cell or tissue, including those stresses caused by tumor growth. Increasing evidence suggests that HSP72 is necessary for a cancerous cell to survive under the stresses of a tumor microenvironment. This has naturally raised interest in identifying an inhibitor selective for HSP72. The Haystead Laboratory at Duke University identified such a small-molecule inhibitor, referred to as HS-72, and proposed the scaffold as an ideal starting point to develop a family of therapeutic agents targeting HSP72. This work examines the potency and effectiveness of HS-72 and a number of its analogs developed by the Haystead Laboratory. These results suggest that HS-159 is a more effective inhibitor of HSP72 on a range of human tumor cell lines than HS-72. Further studies are needed to quantify how much more potent HS-159 is than HS-72 and potentially identify even more potent compounds

The Extracellular Heat Shock Protein 72 Response to a 7-day Desert-based Ultra-marathon

Extracellular heat shock protein 72 (eHsp72) concentration has been shown to significantly increase in response to extreme stress. Ultra-endurance events are becoming increasingly popular and place individuals under a prolonged duration of exercise stress, which is exacerbated when undertaken in extreme environmental conditions, particularly extreme heat. The extreme stress imposed upon the body under such conditions places individuals at increased risk of heat illness and cellular damage. The eHsp72 response to ultra-endurance events in extreme environmental conditions has received little attention and thus research is required to understand the heat shock response to such stress. PURPOSE: To investigate the effect of a desert based ultra-marathon (the Marathon des Sables; MDS) on the eHsp72 response in humans. METHODS: Thirteen (three female) competitors (age 42, range: 23-60 years, height 1.74 ± 0.10 m, mass 77.29 ± 12.92 kg, VO2max 55.25 ± 11.96 ml.kg.min-1) provided blood samples via venepuncture for the measurement of eHsp72 concentration on two occasions prior to the race: i) 12 weeks (baseline), and ii) 7 d (pre-race) prior to departure for the MDS, and two further occasions post-race: iii) ~ 6 h post-race and iv) 7 d post-race. The MDS 2015 consisted of 7 consecutive stages, over 7 d, across the Sahara Desert, Morocco, equating to a total distance of 249.4 km. eHsp72 was determined using a commercially available ELISA kit and is displayed as a percentage change from baseline values. RESULTS: Participants completed the ultra-marathon in an average total time of 3043 ± 1002 min. Post-race eHsp72 concentration was 122%, 117% and 108% greater than baseline, pre-race and 7 d post-race, respectively (F3, 45 = 63.348, p < 0.001). CONCLUSION: eHsp72 concentration is significantly elevated in response to 7 consecutive days of prolonged exercise heat stress in extreme environmental conditions and returns to near baseline values within 7 d post race completion

L-NAME treatment enhances exercise-induced content of myocardial heat shock protein 72 (Hsp72) in rats

Background/Aim: Nitric oxide (NO) modulates the expression of the chaperone Hsp72 in the heart, and exercise stimulates both NO production and myocardial Hsp72 expression. The main purpose of the study was to investigate whether NO interferes with an exercise-induced myocardial Hsp72 expression. Methods: Male Wistar rats (70-100 days) were divided into control (C, n= 12), L-NAME-treated (L, n= 12), exercise (E, n= 13) and exercise plus L-NAME-treated (EL, n= 20) groups. L-NAME was given in drinking water (700 mg. L-1) and the exercise was performed on a treadmill (15-25 m.min(-1), 40-60 min. day(-1)) for seven days. Left ventricle (LV) protein Hsp content, NOS and phosphorylated-NOS (p-NOS) isoforms were measured using Western blotting. The activity of NOS was assayed in LV homogenates by the conversion of [H-3] L-arginine to [H-3] L-citrulline. Results: Hsp72 content was increased significantly (223%; p < 0.05) in the E group compared to the C group, but exercise alone did not alter the NOS content, p-NOS isoforms or NOS activity. Contrary to our expectation, L-NAME enhanced (p < 0.05) the exercise-induced Hsp72 content (EL vs. C, L and E groups = 1019%, 548% and 457%, respectively). Although the EL group had increased stimulatory p-eNOS(Ser1177) (over 200%) and decreased inhibitory p-nNOS(Ser852) (similar to 50%) compared to both the E and L groups (p < 0.05), NOS activity was similar in all groups. Conclusions: Our results suggest that exercise-induced cardiac Hsp72 expression does not depend on NO. Conversely, the in vivo L-NAME treatment enhances exercise-induced Hsp72 production. This effect may be due to an increase in cardiac stress. Copyright (C) 2011 S. Karger AG, Basel275479486CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA E INOVAÇÃO DO ESPÍRITO SANTO - FAPESsem informaçã