Functional characterization of a heat shock factor regulated enhancer at coronary artery disease associated locus that controls CALCRL expression in endothelial cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222118 | GEO | 2024/05/22
REPOSITORIES: GEO
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Project description:Functional characterization of a heat shock factor regulated enhancer at coronary artery disease associated locus that controls CALCRL expression in endothelial cells
| PRJNA918316 | ENA
Project description:Heat shock factor-1 (HSF1) is the central regulator of heat-induced transcriptional responses leading to rapid expression of molecular chaperones that protect mammalian cells against proteotoxic stress. The main targets for HSF1 are specific promoter elements (HSE) located upstream of heat shock genes encoding a variety of heat shock proteins, including HSP70, HSP90, HSP27, and other proteins of the network. Herein we report that the zinc finger AN1-type domain-2a gene, also known as AIRAP, behaves as a canonical heat shock gene, whose expression is temperature-dependent and strictly controlled by HSF1. Transcription is triggered at temperatures above 40 degrees C in different types of human cancer and primary cells, including peripheral blood monocytes. As shown by ChIP analysis, HSF1 is recruited to the AIRAP promoter rapidly after heat treatment, with a kinetics that parallels HSP70 promoter HSF1-recruitment. In transfection experiments HSF1-silencing abolished heat-induced AIRAP promoter-driven transcription, which could be rescued by exogenous Flag-HSF1 expression. The HSF1 binding HSE sequence in the AIRAP promoter critical for heat-induced transcription was identified. Because its expression is induced at febrile temperatures in human cells, AIRAP may represent a new potential component of the protective response during fever in humans.
| S-EPMC2859522 | biostudies-literature
Project description:BackgroundPremature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort.MethodsWe performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis.ResultsAt the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantly greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported.ConclusionsWenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects.
| S-EPMC4736860 | biostudies-literature
Project description:Heat shock locus V (HslV; also called ClpQ) is the proteolytic core of the ATP-dependent protease HslVU in Escherichia coli. It has sequence similarity with the beta-type subunits of the eukaryotic and archaebacterial proteasomes. Unlike these particles, which display 72-point symmetry, it is a dimer of hexamers with 62-point symmetry. The crystal structure of HslV at 3.8-A resolution, determined by isomorphous replacement and symmetry averaging, shows that in spite of the different symmetry of the particle, the fold and the contacts between subunits are conserved. A tripeptide aldehyde inhibitor, acetyl-Leu-Leu-norleucinal, binds to the N-terminal threonine residue of HslV, probably as a hemiacetal, relating HslV also functionally to the proteasomes of archaea and eukaryotes.
| S-EPMC21002 | biostudies-literature
Project description:AimsClinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries.Methods and resultsWhen HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-l-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N-terminal kinase/stress-activated protein kinase, and extracellular signal-regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels.ConclusioncHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction.
| S-EPMC2725775 | biostudies-literature
Project description: Not available
| S-EPMC8375625 | biostudies-literature
Project description:Heat shock proteins are induced by activation of heat shock factor 1 (HSF1) in response to heat shock and protect against heat stress. However, the molecular mechanisms underlying the downstream signal of heat shock have not been fully elucidated. We found that similarly to canonical Hsps, Arc/Arg3.1 is also markedly induced by heat shock and by other cellular stress inducers, including diamide, sodium arsenite and H2O2 in various cells. We noted that heat stress-induced Arc/Arg3.1 protein is short lived, with a half-life of <30 min, and is readily degraded by the ubiquitin-proteasome system. Arc/Arg3.1 overexpression inhibited the up-regulation of heat shock-induced Hsp70 and Hsp27, suggesting that Arc/Arg3.1 is a negative regulator of heat shock response (HSR). Studying the effect of Arc/Arg3.1 on HSF1, a major transcription factor in HSR, we found that Arc/Arg3.1 binds to HSF1 and inhibits its binding to the heat shock element in gene promoters, resulting in reduced induction of Hsp27 and Hsp70 mRNAs, without affecting HSF1's phosphorylation-dependent activation, or nuclear localization. Arc/Arg3.1 overexpression decreased cell survival in response to heat shock. We conclude that Arc/Arg3.1 is transiently expressed after heat shock and negatively regulates HSF1 in the feedback loop of HSR.
| S-EPMC6385231 | biostudies-literature
Project description:Smooth muscle cells (SMCs) go through pehnotypic transition during atherosclerosis progression. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of SMCs in aorta tissuee.
2023-02-03 | GSE214423 | GEO
Project description:BackgroundCoronary artery disease (CAD) is one of the severe diseases that threaten human health worldwide. In addition, the associated rate of comorbidity with depression and anxiety is extremely high. Heat shock proteins (HSPs) are a group of proteins that possesses cardiovascular and psychological protection properties. The objective of this study is to determine the association of the two most widely studied HSPs, namely, HSP70 and HSP90, with CAD comorbid depression and anxiety in a Chinese population.MethodsA case-control study involving 271 CAD patients and 113 healthy individuals was conducted. The 271 CAD patients include individuals with (123) and without depression (148) and individuals with (57) and without anxiety (214). Ten single nucleotide polymorphisms (SNPs) for HSP70 and seven SNPs for HSP90 were selected and genotyped.ResultsResults revealed that the HSP70 rs10892958 C allele and HSP70 rs2236658 T allele were associated with a decreased risk of CAD (P < 0.05), whereas the G allele of the rs11218941 polymorphism was associated with an increased risk of CAD. The haplotype analysis results indicated that the haplotype TGGGC of the HSPA8 gene (coded the HSP70 family, rs4936770/rs4802/rs10892958/rs11218941/rs2236658) significantly increased the risk of CAD (P = 0.008). Among the patients with CAD, the carriers of the CC genotype for the HSP90 rs1042665 showed higher risks of anxiety than the carriers of another genotypes. However, no significant relationships were found among the CAD with depression and CAD without depression groups for the selected SNPs. These findings suggested that the genetic polymorphisms in the HSP gene, especially the HSPA8 of HSP70, contribute to CAD susceptibility and rs1042665 genetic polymorphisms might have an effect on the anxiety incidence among CAD patients.
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Project description:The alpha-crystallins are members of the small heat shock protein family of molecular chaperones that have evolved to minimize intracellular protein aggregation; however, they are also implicated in a number of protein deposition diseases. In this study, we employed novel mass spectrometry techniques to investigate the changes in quaternary structure associated with this switch from chaperone to adjuvant of aggregation. We replicated the oligomeric rearrangements observed for post-translationally modified alpha-crystallins, without altering the protein sequence, by refolding the alpha-crystallins in vitro. This refolding resulted in a loss of dimeric substructure concomitant with an augmentation of substrate affinity. We show that packaging of small heat shock proteins into dimeric units is used to control the level of chaperone function by regulating the exposure of hydrophobic surfaces. We propose that a bias toward monomeric substructure is responsible for the aberrant chaperone behavior associated with the alpha-crystallins in protein deposition diseases.
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