Ventricular tachycardia due to bundle branch reentry: induction by spontaneous atrial premature beats.
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Aged↗
Biomedical subjects
W J Welch
Publications and source records attributed to W J Welch.
Mitogen and lymphokine stimulation of heat shock proteins in T lymphocytes.
We have examined the effects of phytohemagglutinin (PHA) and the polypeptide growth factor interleukin 2 (IL-2) on the synthesis of the 70- and 90-kDa heat shock proteins (HSP70 and HSP90, respectively) in human T lymphocytes. Resting T cells (G0) stimulated with PHA responded with a generalized increase in protein synthesis that included HSP70. Gel blot analysis indicated that steady-state levels of HSP70 mRNA were not specifically modulated by PHA. Synthesis of HSP90 protein, however, peaked very rapidly following PHA stimulation and decreased sharply after 1 hr. When IL-2-dependent human T cells, synchronized by IL-2 deprivation, were treated with IL-2, synthesis of HSP70 mRNA was increased as much as 15-fold. HSP70 and HSP90 protein synthesis increased significantly upon IL-2 stimulation of human T lymphocytes. Two distinct members of the ancient family of heat shock genes, HSP70 and HSP90, are shown to be stimulated at the activation and progression stages of lymphocyte mitogenesis, which suggests that genetic mechanisms evolved from primitive stress/adaptation responses may be conserved in mammalian cellular activation.
Cells, Cultured↗
Characterization of the thermotolerant cell. I. Effects on protein synthesis activity and the regulation of heat-shock protein 70 expression.
Exposure of mammalian cells to a nonlethal heat-shock treatment, followed by a recovery period at 37 degrees C, results in increased cell survival after a subsequent and otherwise lethal heat-shock treatment. Here we characterize this phenomenon, termed acquired thermotolerance, at the level of translation. In a number of different mammalian cell lines given a severe 45 degrees C/30-min shock and then returned to 37 degrees C, protein synthesis was completely inhibited for as long as 5 h. Upon resumption of translational activity, there was a marked induction of heat-shock (or stress) protein synthesis, which continued for several hours. In contrast, cells first made thermotolerant (by a pretreatment consisting of a 43 degrees C/1.5-h shock and further recovery at 37 degrees C) and then presented with the 45 degrees C/30-min shock exhibited considerably less translational inhibition and an overall reduction in the amount of subsequent stress protein synthesis. The acquisition and duration of such "translational tolerance" was correlated with the expression, accumulation, and relative half-lives of the major stress proteins of 72 and 73 kD. Other agents that induce the synthesis of the stress proteins, such as sodium arsenite, similarly resulted in the acquisition of translational tolerance. The probable role of the stress proteins in the acquisition of translational tolerance was further indicated by the inability of the amino acid analogue, L-azetidine 2-carboxylic acid, an inducer of nonfunctional stress proteins, to render cells translationally tolerant. If, however, analogue-treated cells were allowed to recover in normal medium, and hence produce functional stress proteins, full translational tolerance was observed. Finally, we present data indicating that the 72- and 73-kD stress proteins, in contrast to the other major stress proteins (of 110, 90, and 28 kD), are subject to strict regulation in the stressed cell. Quantitation of 72- and 73-kD synthesis after heat-shock treatment under a number of conditions revealed that "titration" of 72/73-kD synthesis in response to stress may represent a mechanism by which the cell monitors its local growth environment.
Animals↗
Characterization of the thermotolerant cell. II. Effects on the intracellular distribution of heat-shock protein 70, intermediate filaments, and small nuclear ribonucleoprotein complexes.
Here we further characterize a number of properties inherent to the thermotolerant cell. In the preceding paper, we showed that the acquisition of the thermotolerant state (by a prior induction of the heat-shock proteins) renders cells translationally tolerant to a subsequent severe heat-shock treatment and thereby results in faster kinetics of both the synthesis and subsequent repression of the stress proteins. Because of the apparent integral role of the 70-kD stress proteins in the acquisition of tolerance, we compared the intracellular distribution of these proteins in both tolerant and nontolerant cells before and after a severe 45 degrees C/30-min shock. In both HeLa and rat embryo fibroblasts, the synthesis and migration of the major stress-induced 72-kD protein into the nucleolus and its subsequent exit was markedly faster in the tolerant cells as compared with the nontolerant cells. Migration of preexisting 72-kD into the nucleolus was shown to be dependent upon heat-shock treatment and independent of active heat-shock protein synthesis. Using both microinjection and immunological techniques, we observed that the constitutive and abundant 73-kD stress protein similarly showed a redistribution from the cytoplasm and nucleus into the nucleolus as a function of heat-shock treatment. We show also that other lesions that occur in cells after heat shock can be prevented or at least minimized if the cells are first made tolerant. Specifically, the heat-induced collapse of the intermediate filament cytoskeleton did not occur in cells rendered thermotolerant. Similarly, the disruption of intranuclear staining patterns of the small nuclear ribonucleoprotein complexes after heat-shock treatment was less apparent in tolerant cells exposed to a subsequent heat-shock treatment.
Animals↗
Regulation of actin microfilament integrity in living nonmuscle cells by the cAMP-dependent protein kinase and the myosin light chain kinase.
Microinjection of the catalytic subunit of cAMP-dependent protein kinase (A-kinase) into living fibroblasts or the treatment of these cells with agents that elevate the intracellular cAMP level caused marked alterations in cell morphology including a rounded phenotype and a complete loss of actin microfilament bundles. These effects were transient and fully reversible. Two-dimensional gel electrophoresis was used to analyze the changes in phosphoproteins from cells injected with A-kinase. These experiments showed that accompanying the disassembly of actin microfilaments, phosphorylation of myosin light chain kinase (MLCK) increased and concomitantly, the phosphorylation of myosin P-light chain decreased. Moreover, inhibiting MLCK activity via microinjection of affinity-purified antibodies specific to native MLCK caused a complete loss of microfilament bundle integrity and a decrease in myosin P-light chain phosphorylation, similar to that seen after injection of A-kinase. These data support the idea that A-kinase may regulate microfilament integrity through the phosphorylation and inhibition of MLCK activity in nonmuscle cells.
Actin Cytoskeleton↗
Dynamic changes in the structure and intracellular locale of the mammalian low-molecular-weight heat shock protein.
Mammalian cells grown at 37 degrees C contain a single low-molecular-weight heat shock (or stress) protein with an apparent mass of 28 kilodaltons (kDa) whose synthesis increases in cells after exposure to elevated temperatures or other forms of physiologic stress. Herein we present data demonstrating that heat shock protein 28 exists in a number of dynamic states depending upon the physiologic state of the cell. Biochemical fractionation of 37 degrees C cells in the absence of nonionic detergent revealed that the 28-kDa protein partitioned approximately equally between the soluble and insoluble fractions. The addition of detergent in the fractionation procedure resulted in all of the protein distributed within the soluble phase. In contrast, in cells first heat shocked and then fractionated in the presence of detergent, most of the 28-kDa protein was found within the insoluble fraction. These biochemical results appeared entirely consistent with indirect immunofluorescence experiments, demonstrating that the 28-kDa protein resided within the perinuclear region of 37 degrees C cells in close proximity to the Golgi complex. After heat shock treatment, the 28-kDa protein relocalized within the nucleus and resisted detergent extraction. The extent of 28-kDa protein redistribution into the nucleus and its detergent insolubility increased as a function of the severity of the heat shock treatment. With time of recovery from the heat treatment there occurred a gradual return of the 28-kDa protein into the detergent-soluble phase. Concomitant with these changes in 28-kDa protein solubility was a corresponding change in the apparent size of the protein as determined by gel filtration. While at 37 degrees C cells the protein exhibited a mass of 200 to 800 kDa; after heat shock the protein assumed sizes of 2 MDa or greater. Using immunoelectron microscopy, we show an accumulation of these aggregates of 28-kDa protein within the nucleus. Finally, we show that the heat-dependent redistribution of the 28-kDa protein from the cytoplasm into the nucleus was greatly diminished when the cells were first rendered thermotolerant, and we suggest that this simple assay (i.e., 28-kDa protein detergent solubility) may prove useful in evaluating the thermotolerant status of a cell or tissue.
Fibroblasts↗
Modulating role for thromboxane in the tubuloglomerular feedback response in the rat.
Some studies have indicated that PGs can modulate the single nephron tubuloglomerular feedback (TGF) response. The aim of this study was to define the specific role of the vasoconstrictor PG, TX, by administration to rats of either vehicle (group 1; n = 20) or drugs that inhibit either cyclooxygenase (indomethacin [indo], 5 mg.kg-1, group 2, n = 17), TX synthetase (UK-38,485 [UK], 100 mg.kg-1, group 3, n = 19), or TX receptors (SQ-29,548 [SQ], 8 mg.kg-1, group 4, n = 14, or L-641,953 [L], 50 mg.kg-1, group 5, n = 8). Indo reduced excretion of the prostacyclin derivative 6-keto-PGF1 alpha and TXB2 and lowered whole kidney GFR and renal plasma flow, whereas UK lowered excretion of TXB2 only and did not change basal renal hemodynamics. The TGF response (assessed from reduction in proximal tubule stop-flow pressure (Psf, mmHg) during increases in perfusion of the loop of Henle (LH) from 0 to 40 nl.min-1) was unchanged after vehicle (9.8 +/- 0.5-10.9 +/- 1.0, NS) but blunted (P less than 0.001) by 40-65% in rats of groups 2-5 (indo, 11.1 +/- 1.0-4.4 +/- 0.7; UK, 9.0 +/- 0.8-4.8 +/- 0.7; SQ, 10.3 +/- 0.6-4.8 +/- 0.6; L, 10.7 +/- 0.5-6.7 +/- 1.3). This blunting was due to lower values for Psf at zero LH flow after indo, SQ, and L, and higher values of Psf at 40 nl.min-1 LH flow after indo and UK. The fall in single nephron GFR (SNGFR, nl.min-1) with increasing LH perfusion was unchanged after vehicle (10.9 +/- 2.8-11.2 +/- 0.8) but was blunted (P less than 0.05) by 45-55% in rats given indo (13.9 +/- 1.2-6.2 +/- 2.2) or UK (12.8 +/- 2.1-7.0 +/- 1.5). UK produced dose-dependent reductions in TXB2 excretion (IC50, 15 mg.kg-1) and inhibition of the TGF response (IC50: 30 mg.kg-1). After blockade of TX receptors by SQ, UK had no further affect on the TGF response. The fall in Psf at high LH flow was blunted (P less than 0.05) by indo and UK, whereas the rise in Psf at zero LH flow was blunted by indo, SQ, and L. In conclusion, endogenous TX generation can modulate the reductions in Psf and SNGFR during increased delivery of NaCl to the LH.
Analysis of Variance↗
Characterization and purification of the small 28,000-dalton mammalian heat shock protein.
We describe the biochemical characterization and purification of the small 28,000-dalton heat shock protein (28-kDa protein) of mammalian cells. Metabolic pulse labeling of heat shock-treated cells with either [3H]leucine or H3 32PO4 and analysis of the labeled proteins by two-dimensional gel electrophoresis revealed increased levels of three 28-kDa proteins differing only in their relative isoelectric point. Using both peptide mapping and immunological analysis, we demonstrate that all three proteins are related isoforms, with two of the isoforms containing phosphate. Cell fractionation studies revealed that the 28-kDa protein localizes predominantly within the nuclear pellet very shortly after the heat shock treatment. With increasing times of recovery of the heat-treated cells back at 37 degrees C, the majority of the 28-kDa protein was now observed to fractionate within the soluble fraction of the cells. Both gel filtration and velocity sedimentation studies revealed that the 28-kDA protein exists as a higher order structure with an approximate S20,w value of 10-18 S, a Stokes radius of about 60-70 A, and an estimated native molecular mass of at least 500,000 daltons. We describe a relatively simple and rapid purification of the proteins employing both ion-exchange and gel filtration chromatography.
Electrophoresis, Polyacrylamide Gel↗
The mammalian heat shock (or stress) response: a cellular defense mechanism.
The response of mammalian cells to abrupt changes in their local environment entails a series of coordinated transcription and translation events leading to the accumulation of a group of proteins, the stress proteins. As evidenced by the high similarities in the structure of the stress proteins amongst different organisms, the stress response appears to be a well-conserved, pre-planned strategy by which cells protect themselves against changes in their environmental circumstance. In addition to their presumed protective role, most of the stress proteins are expressed at significant levels in cells grown under normal conditions and participate in a number of biological phenomenon apparently distinct from their role during stress. For example, we have described here the role of some of the stress proteins in clathrin coated vesicle assembly/disassembly, tyrosine kinase and steroid hormone receptor function, and cell proliferation. In this regard it seems likely that we have only touched the surface regarding the many different biological processes which occur normally in cells and which involve the participation of the individual stress proteins. Of particular importance, as well, is to understand the role of the stress proteins, both individually and collectively, in protecting the cell during and after recovery from physiological stress. A breakthrough in this endeavor has come from the recent observation demonstrating the structural and biochemical similarities of many of the stress proteins and notably their ability to bind ATP. In this regard, I have described the immunological and biochemical similarities of the 70 kDa heat shock proteins with that of the 80 kDa glucose regulated protein and suggest that this family of proteins serves basically similar functions but within different intracellular compartments: the 70 kDa proteins being cytosolic and nuclear and 80 kDa being present within the endoplasmic reticulum. That a general rule is emerging here comes from the recent observation of Sorger and Pelham (in press) describing a significant sequence homology of the 90 kDa heat shock protein with that of the other glucose-regulated protein, 100 kDa. Here again, however, the proteins are distributed differently: 90 kDa is a soluble cytoplasmic protein and 100 kDa is present within the Golgi and perhaps the plasma membrane (Welch et al., 1984). Might all of the stress proteins have evolved from only a few genes with selection having resulted in different compartmentalization of the stress proteins?(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Triphosphate↗
Medium tumor antigen of polyomavirus transformation-defective mutant NG59 is associated with 73-kilodalton heat shock protein.
Affinity-purified medium T antigen encoded by NG59, a nontransforming mutant of polyomavirus, is specifically associated with a protein of 72,000 daltons (72K protein). Medium T antigens of wild-type polyomavirus and the transformation-competent mutant dl8 are not associated with the 72K protein. Instead, they form a complex with another protein of 61,000 daltons. Several lines of evidence suggest that the medium T antigen-associated 72K protein is equivalent to the abundant and constitutive 73K heat shock protein. First, on two-dimensional polyacrylamide gels the 72K protein migrated with the same pI (5.6) as did the 73K heat shock protein. Second, the 72K protein was immunoprecipitable with antibodies against heat shock proteins. Third, when digested with V8 protease, the 72K protein gave rise to the same pattern of fragments as did the 73K heat shock protein.
Animals↗
Control of renin release by dietary NaCl in the rat.
The purpose of the present study is to determine whether changes of plasma renin activity (PRA) induced by dietary NaCl are mediated by a renal tubular mechanism or by a neural mechanism. Male Sprague-Dawley rats were placed on low-, normal-, or high-NaCl diets for 1 wk (n = 8 for each group). There were no group differences of glomerular filtration rate (GFR), renal plasma flow, Na+ or Cl- delivery to the loop, Na+ or Cl- reabsorption in the loop, Na+ or Cl- concentration in early distal tubular fluid, or Na+ or Cl- delivery to the early distal tubule. PRA of rats on normal NaCl (4.8 ng.ml-1.h-1 +/- 0.8) was greater (P less than 0.05) than that of rats on high NaCl (3.3 +/- 0.4) and less (P less than 0.05) than that of animals on low NaCl (9.1 +/- 1.8). To determine whether alterations of PRA by dietary NaCl might be related to low-pressure baroreceptors with vagal afferents, animals were bilaterally vagotomized after micropuncture. Forty-five minutes after vagotomy, PRA increased (P less than 0.05) on each of the diets, however, after vagotomy mean PRA in animals fed normal (10.9 +/- 1.8) and low NaCl (13.2 +/- 2.2) did not differ. Thus our results do not support the hypothesis that suppression of PRA by dietary NaCl loading is related to a renal tubular mechanism. A vagally mediated mechanism may contribute to renin suppression by dietary NaCl.
Animals↗
Mutant p53 proteins bind hsp 72/73 cellular heat shock-related proteins in SV40-transformed monkey cells.
We have examined the expression of a series of mouse mutant, as well as wild-type, p53 proteins in SV40-transformed monkey COS cells. Wild-type mouse p53 binds predominantly to SV40 large T antigen in these cells. However, several of the mutants co-precipitate exclusively with proteins of approximately 68 Kd relative molecular mass. We show by immunological and proteolytic mapping techniques that these proteins are identical to the hsp 72/73 heat shock proteins. p53 mutants in complex with hsp 72/73 have an altered subcellular location compared to the wild-type protein and the hsp 72/73 binding p53 mutants fail to exhibit an epitope recognized by monoclonal antibody PAb 246. The existence of at least two antigenically distinct subclasses of hsp 72/73 complexed to mutant p53 is shown.
Animals↗
Renal tubular chloride and renin release.
We have suggested that the renal tubular signal for renin release is related to alterations of sodium chloride cotransport in the TALH. Renin release is inhibited by increased sodium chloride transport and stimulated by interrupted sodium chloride transport. Because of the different affinities of the carriers for sodium and chloride, chloride rather than sodium is rate limiting for this cotransport process. Consequently, renin release is related to alterations of chloride delivery rather than sodium delivery to the TALH. The reduction of PRA by selective chloride loading and by short-term infusion of chloride salts is related to increased chloride delivery to the loop and hence increased chloride transport. Alternatively, chlorpropamide and antidiuretic hormone may inhibit renin release by increasing chloride delivery to the loop. Stimulation of renin release may likewise be related either to decreased chloride delivery and hence decreased transport in the loop (hypochloremia related to selective chloride deprivation) or to an intrinsic alteration in the transporting capacity of the loop (loop diuretics, potassium depletion, glucocorticoid deficiency, Bartter's syndrome). The intermediate steps between alterations of sodium chloride transport in the TALH and renin release remain to be defined.
Animals↗
A cloud collision model for water maser excitation.
High-velocity collisions between small, dense, neutral clouds or between a dense cloud and a dense shell can provide the energy source required to excite H2O maser emission. The radiative precursor from the surface of the collisional shock front rapidly diffuses through the cloud, heating the dust grains but leaving the H2 molecules cool. Transient maser emission occurs as the conditions for the Goldreich and Kwan "hot-dust cold-gas" maser pump scheme are realized locally within the cloud. In time the local maser action quenches due to the heating of the H2 molecules by collisions against the grains. Although this model cannot explain the very long-lived steady maser features, it is quite successful in explaining a number of the observed properties of the high-velocity features in such sources as Orion, W51, and W49. In particular, it provides a natural explanation for the rapid time variations, the narrow line widths, juxtaposition of high- and low-velocity features, and the short lifetimes which are frequently observed for the so-called high-velocity maser "bullets" thought to be accelerated by strong stellar winds.
Astronomical Phenomena↗
Uncoating ATPase is a member of the 70 kilodalton family of stress proteins.
The synthetic peptide, VGIDLGTTYSC, derived from the heat shock-induced genes human hsp70, Drosophila hsp70, S. cerevisiae YG100, and E. coli dnaK, elicited antibodies that recognized two constitutive proteins in bovine extracts. One of these proteins, 71 kd, has previously been identified as uncoating ATPase, an enzyme that releases clathrin from coated vesicles. This immunological data complemented the result that uncoating ATPase was indistinguishable from the constitutive mammalian 71 kd stress protein by either partial proteolytic mapping or two-dimensional gel analysis. In addition, affinity-purified uncoating ATPase antibodies recognize proteins in yeast identified as the gene products of the heat shock or heat shock cognate genes YG100 and YG102. The results show that uncoating ATPase is a member of the 70 kd heat shock protein family.
Adenosine Diphosphate Ribose↗
Long-term therapy with disopyramide phosphate: side effects and effectiveness.
In this study, the safety and efficacy of long-term therapy with disopyramide phosphate were evaluated in 40 patients with documented, recurrent, symptomatic tachyarrhythmias. Twenty-one (53%) of the patients had organic heart disease, and nine of these patients had compensated congestive heart failure. The tachyarrhythmias which were treated were paroxysmal supraventricular tachycardia (21 patients), paroxysmal atrial fibrillation (six patients), and paroxysmal ventricular tachycardia (13 patients). In each patient there was evidence, from continuous ECG monitoring or electrophysiologic testing, that disopyramide would be effective therapy, and each patient was able to tolerate disopyramide (no side effects or tolerable side effects) during an initial trial period of 1 to 2 weeks. Dosages of disopyramide were 400 to 1600 mg/day (994 +/- 320 mm/day). During long-term therapy, side effects were reported by 28 (70%) of the patients. The side effects were usually anticholinergic, and were usually a continuation of side effects noted during the initial trial period. None of the patients had idiosyncratic reactions to disopyramide. Most of the patients found side effects to be tolerable; however, in seven patients it was necessary to discontinue disopyramide after 1 to 8 (6 +/- 3) months. Actuarial incidence of intolerable side effects was 21 +/- 7% at 12 months. Nine (22%) of the 40 patients had symptomatic recurrences of tachyarrhythmia after 3 to 32 (15 +/- 9) months of therapy. Actuarial incidence of drug ineffectiveness was 32 +/- 10% at 24 months. Disopyramide was both effective and tolerated in 24 (60%) of the patients, who were followed for 2 to 64 (23 +/- 16) months.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Paroxysmal fascicular tachycardia and ventricular tachycardia due to mechanical stimulation by a mitral valve prosthesis.
Electrophysiologic studies were performed in a woman who had two varieties of paroxysmal wide QRS tachycardia after mitral valve replacement with a Starr-Edwards prosthesis. One tachycardia originated in the left anterior fascicle; QRS complexes were 100 ms wide and resembled right bundle branch block with left posterior fascicular block, and a His bundle potential preceded each QRS by an interval of 20 ms (compared with 50 ms during sinus rhythm). The other tachycardia originated in the left ventricle. Clinical and echocardiographic observations suggested that the tachycardias were caused by mechanical stimulation of the interventricular septum by the mitral prosthesis.
Adult↗
Tachyarrhythmias in young athletes.
Nineteen young athletes with documented symptomatic tachyarrhythmia were systematically evaluated. There were 15 men and 4 women, aged 14 to 32 years (mean 22 +/- 6). Documented tachyarrhythmias were paroxysmal atrial fibrillation in five patients, paroxysmal supraventricular tachycardia in five, paroxysmal ventricular tachycardia in eight (sustained in five, nonsustained in three) and ventricular fibrillation in one patient. Abnormal substrates were demonstrated in 15 (79%) of the 19 athletes: 5 had an anomalous atrioventricular (AV) pathway and 10 had heart disease (mitral valve prolapse in 9 patients and dilated cardiomyopathy in 1 patient). In 13 (68%) of the 19 athletes, all spontaneous attacks of tachyarrhythmia had started during strenuous exercise. Tachyarrhythmia that closely resembled clinical arrhythmia was induced by programmed cardiac stimulation in 13 athletes (68%) and was reproducibly provoked by treadmill exercise in 8 athletes (42%). In four of seven athletes with ventricular tachycardia, tachycardia closely resembling clinical arrhythmia was provoked by infusion of isoproterenol. In summary: young athletes can have any of several tachyarrhythmias; abnormal substrates can be demonstrated in many athletes with symptomatic tachyarrhythmia; and tachyarrhythmias in young athletes frequently occur during exercise.
Adolescent↗