Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While heat shock protein (HSP) 72 is known as a stress protein, there have been no reports of HSP 72 expression in patients who have undergone surgery for congenital heart disease. Fourteen patients (7 males and 7 females) who had undergone surgery for congenital heart disease were studied. The ages of the patients ranged from 2 months to 43 years old (mean 6.5 +/- 10.8 years old; median 3.0 years old). The diagnoses were Tetralogy of Fallot in seven, pulmonary atresia with ventricular septal defect (VSD) in three, complex anomalies in three, and VSD in one patient. Histological study and HSP analysis using Western blots and immunostaining with anti-HSP 72 monoclonal antibody were performed for right ventricular muscle samples resected during the surgery. The histological findings showed hypertrophic changes of ventricular cardiomyocytes in all samples studied. Western blots detected HSP 72 expression of various degrees in all specimens. Immunostaining using monoclonal antibody against HSP 72 showed that the protein was present in the nuclei and cytoplasm of cardiomyocytes. In conclusion, although it is difficult to determine the cause of the "stress" that triggers HSP 72 expression in cardiomyocytes, low O2 saturation and pressure overload might act as a "stress", and the only common factor that induced HSP 72 in every sample was hypertrophy.
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PMID:Heat shock protein 72 expression in the right ventricle of patients undergoing congenital cardiac surgery. 1092 34

Exercise is a physiological inducer of the cardioprotective heat shock protein, Hsp70. The putative biological events involved in signaling this response exhibit sexual dimorphism. Thus, it was hypothesized that exercise-mediated induction of Hsp70 would demonstrate sex specificity. After treadmill running, male rats exhibited 2-fold greater levels of cardiac Hsp70 relative to the levels in gonadally intact female rats (P<0.001). Ovariectomized female rats exhibited exercise-mediated induction of Hsp70 similar to that observed for male rats, and estrogen treatment in these female rats reversed this effect (P<0.001). Attenuation of Hsp70 signaling by estrogen was non-receptor-mediated, possibly involving a cellular membrane-stabilizing mechanism of action. The physiological importance of this sex-specific hormone-mediated stress response is underscored by the disparity in functional adaptation in response to exercise between male rats and female rats. Exercise markedly improved postischemic left ventricular developed pressure, the maximal rate of contraction, and maximal rate of relaxation, and it reduced left ventricular end-diastolic pressure in male rats (P<0.001). No such benefit of exercise was observed in intact female rats. A causal role for Hsp70 in this sex-specific cardioprotective adaptation was indicated, inasmuch as ablation of Hsp70 induction with antisense oligonucleotides designed against Hsp70 transcripts attenuated improvement in the recovery of cardiac function in exercised male rats (P<0.05). Thus, the sex-specific hormone-mediated Hsp70 response to exercise results in cardioprotective adaptation, preferentially in male rats relative to female rats. These findings suggest that exercise may be more important for males than for females in defending against the effects of heart disease and offer a novel manner by which males may reduce the sex gap in susceptibility to adverse cardiac events.
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PMID:Exercise improves postischemic cardiac function in males but not females: consequences of a novel sex-specific heat shock protein 70 response. 1216 55

In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.
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PMID:The stress response: implications for the clinical development of hsp90 inhibitors. 1452 86

Chlamydia pneumoniae (C. p.) is very frequently cited as an important factor of the origin of atherosclerosis. To confirm the diagnostic value of the serological examination the following reactions have been used: microimmunofluorescence reaction (MIF) for estimating of antibodies against major outer membrane proteins C. p. (anti-MOMP) and ELISA for detecting antibodies against the lipopolysacharides of C. p. (anti-LPS), both in IgA and IgG immunoglobulin classes of the serum. The ELISA for the detection of the IgG antibodies against chlamydial heat shock protein (cHSP60) has been used. The sera of 155 patients suffering from acute myocardial infarction (AMI) and 69 patients with unstable angina pectoris (UAP) have been examined. The heart disease has been confirmed by anamnesis, electrocardiography and coronarography. As a control group the sera from 112 persons without sings of a heart disease were examined. The antibodies against the cHSP60 have been determined only in the sera 69 patients with UAP and 49 control sera. Statistically higher occurrence of the antibodies anti-MOMP C. p. in the IgA class sera of patients suffering from UAP has been noted compared with those found in the sera of the control group (chi 2 = 18.56; p < 0.01). In the globulin IgG class of the both groups no difference has been found. The anti-LPS C. p. antibodies in the IgA as well in IgG anti-LPS classes of the patients sera with UAP were present significantly more frequently than in the control group (chi 2 = 11.49; p < 0.01, chi 2 = 4.16; p < 0.05). Similarly the incidence of the anti-LPS C. p. antibodies in the IgA class sera of 155 patients suffering from AMI was significantly higher than in the control group (chi 2 = 8.55; p < 0.01). The anti-cHSP60 antibodies have been found in 41 out of 69 patients suffering from UAP (59.4%) and in 21 of 49 control individuals (42.9%). The results seem to confirm an important role of C. p. in atherogenesis. The monitoring of the antibodies against the C. p. may supplement the diagnostics in patients suffering from UAP and AMI and the efficacy of its therapy and prevention as well.
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PMID:[Serologic study of atherosclerosis and its vascular complications]. 1466 61

H11 kinase (H11K) is a small heat shock protein expressed predominantly in the heart and skeletal muscle, which plays a critical role in the maintenance of cardiac cell survival and in promoting cell growth through the activation of complementary signaling pathways. An overexpression of H11K was detected in various forms of heart disease, both in animal models and in patients, including acute and chronic ventricular dysfunction, and myocardial hypertrophy. Overexpression of H11K was reproduced in a cardiac-specific transgenic model, which led to significant progress in understanding the role and mechanism of action of the protein. Increased expression of H11K confers a cardioprotection that is equivalent to ischemic preconditioning; it promotes cardiac hypertrophy while maintaining contractile function. The overexpression of H11K is sufficient to activate most of the signaling pathways involved in cardiac cell growth and survival, including the phosphatidylinositol-3-kinase/Akt pathway, the AMP-dependent protein kinase, the PKCepsilon pathway of ischemic preconditioning, the nitric oxide pathway of delayed cardioprotection, and the mTOR pathway of cell growth. As a result, the survival response triggered by H11K in the heart includes antiapoptosis, cytoprotection, preconditioning, growth, and metabolic stimulation. In addition to activating signaling pathways, H11K promotes the subcellular translocation and crosstalk of intracellular messengers. This review discusses the biological function of H11K, its molecular mechanisms of action, and its potential therapeutic relevance. In particular, we discuss how preemptive conditioning of the heart by H11K might be beneficial for patients with ischemic heart disease who would be at risk of further irreversible cardiac damage.
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PMID:Therapeutic potential of H11 kinase for the ischemic heart. 1744 85

The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (I(Kr)). In order to search for HERG-interacting proteins important for HERG maturation and trafficking, we conducted a proteomics screen using myc-tagged HERG transfected into cardiac (HL-1) and non-cardiac (human embryonic kidney 293) cell lines. A partial list of putative HERG-interacting proteins includes several known components of the cytosolic chaperone system, including Hsc70 (70-kDa heat shock cognate protein), Hsp90 (90-kDa heat shock protein), Hdj-2, Hop (Hsp-organizing protein), and Bag-2 (BCL-associated athanogene 2). In addition, two membrane-integrated proteins were identified, calnexin and FKBP38 (38-kDa FK506-binding protein, FKBP8). We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system. Importantly, small interfering RNA knock down of FKBP38 causes a reduction of HERG trafficking, and overexpression of FKBP38 is able to partially rescue the LQT2 trafficking mutant F805C. We propose that FKBP38 is a co-chaperone of HERG and contributes via the Hsc70/Hsp90 chaperone system to the trafficking of wild type and mutant HERG potassium channels.
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PMID:Co-chaperone FKBP38 promotes HERG trafficking. 1756 59

The small heat shock protein Hsp20 protects cardiomyocytes against apoptosis, and phosphorylation at its Ser16 site enhances its cardioprotection. To determine whether genetic variants exist in human Hsp20, which may modify these beneficial effects, we sequenced the coding region of the Hsp20 gene in 1347 patients suffering from dilated cardiomyopathy and 744 subjects with no heart disease. We identified a C59T substitution in the human Hsp20 gene in one patient and three individuals without heart disease. All subjects were heterozygous for this mutation, which changes a fully conserved proline residue into leucine at position 20 (P20L), resulting in secondary structural alterations. To examine the potential functional significance of the P20L-Hsp20 human variant, adult rat cardiomyocytes were infected with Ad.GFP (where Ad is adenovirus and GFP is green fluorescent protein), Ad.WT-Hsp20 (where WT is wild-type), and Ad.P20L-Hsp20 and subjected to simulated ischemia/reperfusion injury. Expression of WT-Hsp20 resulted in significant attenuation of apoptosis compared with the GFP control. However, the P20L-Hsp20 mutant showed no protection against apoptosis, assessed by Hoechst staining and DNA fragmentation. The loss of cardioprotection by the mutant Hsp20 was associated with its diminished phosphorylation at Ser16 compared with WT-Hsp20. Furthermore, maximal stimulation of cardiomyocytes with isoproterenol or protein kinase A-mediated phosphorylation in vitro confirmed the impaired ability of the mutant Hsp20 to become phosphorylated at Ser16. In conclusion, we have identified a P20L substitution in human Hsp20, which is associated with diminished phosphorylation at Ser16 and complete abrogation of the Hsp20 cardioprotective effects which may adversely affect the ability of human carriers to cope with cellular stress.
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PMID:Human mutation in the anti-apoptotic heat shock protein 20 abrogates its cardioprotective effects. 1879 Jul 32

Endurance training improves cardiac function and protects against heart disease. The rodent intensity-controlled running model replicates endurance exercise in humans and can be used to investigate molecular adaptations in the heart. Rats (n = 6, 280 +/- 3 g) performed exercise tests to measure their peak oxygen uptake (VO2peak) and training was prescribed at 70-75% VO2 peak for 30 min, 4 days/wk. Hearts were isolated 4 h after a final VO2peak test and left ventricle proteomes compared to weight-matched control animals (n = 6, 330 +/- 2 g) using differential analysis of 2-D gels. Proteins were identified by searching MS and MS/MS spectra against Swiss-Prot using MASCOT (www.matrixscience.com). Average VO2peak increased 23% (p = 0.008) over the 6-week regimen and 23 gel spots differed (p<0.05) between exercised and control hearts. Expression of myofibrillar proteins (e.g. alpha-myosin heavy chain and cardiac alpha-actin) and proteins associated with fatty acid metabolism (e.g. heart fatty acid binding protein, acetyl coenzyme A dehydrogenase and mitochondrial thioesterase-1) increased. In addition, this work discovered a novel increase in phosphorylation of heat shock protein 20 at serine 16. Previously this modification has been associated with improved cardiomyocyte contractility and protection against apoptosis.
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PMID:Adaptation of the rat cardiac proteome in response to intensity-controlled endurance exercise. 1905 38

Even though exhaustive exercise-induced oxidative stress increases the risk of tissue damage, regular endurance training is widely assumed to improve cardiac function and protects against heart disease. We tested the hypothesis that an endurance training program prevents exhaustive exercise-induced increases in cardiac dysfunction and apoptosis in left ventricle (LV). Thirty-two male Sprague-Dawley rats were randomly divided into four groups: sedentary control (C), trained (T), exhaustively exercised (E), and trained plus exhaustively exercised (TE). Rats in T and TE groups ran on a motorized treadmill for 12 weeks. Rats in groups E and TE performed an exhaustive running test on a treadmill. The main effects of training were indicated by increased running time to exhaustion (80 +/- 5 and 151 +/- 13 min for groups E and TE, respectively, P = 0.0001), myocardial hypertrophy (0.38% and 0.47% for untrained and trained rats, respectively, P = 0.0002), decreased LV ejection fraction (88% and 71% for untrained and trained rats, respectively, P < 0.0001), accelerated mitochondrial DNA 4834-bp large deletion (mtDNA4834 deletion), and up-regulated protein levels of heat shock protein-70, cytochrome C, cleaved capsase-3, and cleaved PARP in LV following a bout of exhaustive exercise. Contrary to our hypothesis, these results suggest that endurance training induced significant impairment of regional systolic and diastolic LV myocardial function and ejection fraction in rats. Our findings show that endurance training accelerates exhaustive exercise-induced mtDNA4834 deletion and apoptosis in the LV.
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PMID:Endurance training accelerates exhaustive exercise-induced mitochondrial DNA deletion and apoptosis of left ventricle myocardium in rats. 1973 Aug 78

We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH(4)) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein-90 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5'-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH(4), may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90-GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH(4) concentrations. We also found in vivo that Hsp90/GCH1 interactions are decreased, whereas GCH1-Hsp70 and GCH1-CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90-GCH1 interactions and increased both BH(4) and NO(x) concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH(4) concentrations, secondary to the disruption of Hsp90-GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.
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PMID:C-terminus of heat shock protein 70-interacting protein-dependent GTP cyclohydrolase I degradation in lambs with increased pulmonary blood flow. 2087 Aug 96


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