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Biomedical subjects

M J Dunn

Publications and source records attributed to M J Dunn.

At least 127 records · Page 7Linked to original sources
PubMed1994

Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.

Animals↗
PubMed1994

Complement-mediated cytotoxic activity of anti-heart antibodies present in the sera of patients with dilated cardiomyopathy.

A microcytotoxicity assay has been used to determine the cytotoxic activity of anti-heart antibodies which we have previously shown to be present with greater frequencies and reactivities in patients with dilated cardiomyopathy (DCM) than in patients with ischaemic heart disease (IHD). Serum samples from 45 patients with DCM and 43 patients with IHD were screened against W1, a transformed human fetal cardiac cell line and also against EA.hy 926, an endothelial and IBR3, a fibroblast cell line. In the presence of complement, sera from 28 (62%) DCM patients showed killing of the W1 cell line as compared to sera from 13 (30%) of IHD patients (p < 0.005) and 3 (15%) of normal individuals. In contrast, only 1 patient with DCM showed killing of the endothelial cell line and 1 patient with IHD showed killing of the fibroblast cell line. These results provide evidence for a complement-dependent, antibody-mediated mechanism of damage to cardiac myocytes which may contribute to the pathogenesis of DCM.

Adolescent↗
PubMed1993

Frequency and specificity of antiheart antibodies in patients with dilated cardiomyopathy detected using SDS-PAGE and western blotting.

OBJECTIVES: This study was designed to investigate the organ and disease specificity of antiheart antibodies in patients with dilated cardiomyopathy. BACKGROUND: Autoimmune disease is characterized by the presence of circulating autoantibodies, and autoimmune mechanisms may play a role in the pathogenesis of dilated cardiomyopathy. METHODS: An SDS-PAGE (sodium dodecylsulfate polyacrylamide gel electrophoresis) procedure followed by Western blotting was used to screen serum samples for antiheart antibodies of two immunoglobulin classes, IgM and IgG, from 52 patients with dilated cardiomyopathy and 48 patients with ischemic heart disease as control subjects. Use of two-dimensional gel electrophoresis followed by Western blotting and protein sequencing enabled us to identify the protein bands against which antiheart antibodies were produced in both groups of patients. RESULTS: Strong IgG antiheart antibodies against myocardial proteins, cross-reacting with skeletal muscle proteins, were detected in significantly more patients with dilated cardiomyopathy (n = 24 [46%]) than with ischemic heart disease (n = 8 [17%]) (p = 0.001). Patients with dilated cardiomyopathy showed a significantly greater frequency and reactivity of IgG antiheart antibodies against six myocardial proteins (molecular weight 30, 35, 40, 60, 85 and 200 kD) than did patients with ischemic heart disease. These were identified as myosin light chain 1, tropomyosin, actin, heat shock protein (HSP)-60, an unidentified protein and myosin heavy chain, respectively. CONCLUSIONS: We detected strong IgG antiheart antibodies in significantly more patients with dilated cardiomyopathy than with ischemic heart disease. The most immunogenic band was that corresponding to HSP-60. Antibodies against HSP-60 were found in 85% and 42% of patients with dilated cardiomyopathy and ischemic heart disease, respectively, confirming our hypothesis of an immune involvement in dilated cardiomyopathy.

Actins↗
PubMed1993

Manidipine inhibits endothelin-1-induced [Ca2+]i signaling but potentiates endothelin's effect on c-fos and c-jun induction in vascular smooth muscle and glomerular mesangial cells.

We studied the effects of manidipine, a newly synthesized dihydropyridine Ca2+ channel antagonist, on endothelin-1 (ET-1)-induced [Ca2+]i signaling and immediate-early gene induction in vascular smooth muscle A7r5 cells and glomerular mesangial cells (MCs). ET-1-induced a dose-dependent, biphasic increase in [Ca2+]i in both A7r5 cells and MCs. Manidipine inhibited the ET-1-induced [Ca2+]i increase by reducing both the transient and sustained Ca2+ increments in A7r5 cells and MCs. At concentrations of 10(-10) to 10(-6) mol/L, inhibition was dose dependent with a median effective dose (ED50) of 10(-9) mol/L. A 20-minute preincubation period was required to observe the maximal inhibitory effect of manidipine. In contrast, manidipine (10(-5) mol/L) potentiated ET-1-induced c-fos and c-jun expression in A7r5 cells. This potentiating effect appeared 30 minutes after manidipine was added to the media and lasted for 15 hours. Manidipine alone had no detectable effect on c-fos steady-state messenger ribonucleic acid level. Manidipine induced c-jun expression starting at 60 minutes but with much lower potency. These data demonstrate that manidipine is a potent inhibitor for ET-1-induced [Ca2+]i signaling and that manidipine has multiple effects on ET-1-induced signaling, including potentiating the immediate-early gene response.

Animals↗
PubMed1993

Endothelin stimulates mitogen-activated protein kinase p42 activity through the phosphorylation of the kinase in rat mesangial cells.

We have reported that endothelin-1 (ET-1), which is a constrictor and mitogenic peptide, can increase mitogen-activated protein kinase p42 (p42mapk) activity in rat mesangial cells. In this study, we investigate the mechanism of activation of p42mapk. Treatment of quiescent mesangial cells with 10(-7) M ET-1 biphasically stimulated p42mapk activity. The kinetics of the immunoprecipitated p42mapk activity induced by ET-1 showed a maximal 3.5- to 4.5-fold stimulation 5 min after the addition of the agonist to the cell cultures and a smaller, 2.5-fold increase of activity between 2 and 6 h after ET challenge. Neither peak of p42mapk activity induced by ET-1 was inhibited by pretreatment of the cells with either cycloheximide to inhibit protein synthesis or actinomycin D to retard transcription. Analysis by immunoblot showed that p42mapk was not affected by these pretreatments. In addition, the kinetics of phosphorylation of p42mapk showed a significant 32P incorporation into p42 at 5, 30, and 240 min after ET stimulation. Because phosphorylation on tyrosine and threonine residues of the enzyme is necessary for activation of the kinase, we believe that the phosphorylation of the p42mapk rather than transcriptional or translational induction is responsible for the activation of p42mapk in mesangial cells stimulated with ET-1.

Animals↗
PubMed1993

Renal actions of endothelin peptides.

In the past year, major advances have been made in understanding the role of endothelin peptides in renal homeostasis. Numerous cells in the kidney secrete endothelin, which binds to two receptor subtypes on neighboring cells in an autocrine or paracrine mode. Endothelin is a potent vasoconstrictor of the renal vasculature that reduces renal blood flow and glomerular filtration rate. Endothelin also affects renal sodium and water handling. Finally, we may have to extend our concept of the renal actions of endothelin to include its growth factor actions.

Amino Acid Sequence↗
PubMed1993

Compliance in the care of disposable contact lenses: the effect of patients' health beliefs.

We used Becker and Maiman's Health Belief Model to study the compliance of 100 disposable contact lens patients using a recommended lens care routine. Compliance was defined as continuous lens wear for no more than two consecutive weeks. A telephone survey found 90 of 100 patients to be complaint. Unexpectedly, 62% of patients removed and then reinserted the same pair of lenses. No significant difference was found between the complaint and noncompliant groups with respect to their health beliefs. Seven percent of the patients reported having experienced corneal complications and 8% reported eye infections. However, a review of these patients' charts showed that only 3% had been diagnosed as having corneal abrasions, and none had been diagnosed as having an eye infection.

Adult↗
PubMed1993

Role of catalase and heat shock protein on recovery of cardiac endothelial and mechanical function after ischemia.

The aim of this study was to investigate the roles of heat shock proteins and catalase after heat shock stress in the recovery of cardiac mechanical and endothelial function following a prolonged ischemic, cardioplegic arrest. Isolated working rat hearts were subjected to an ischemic cardioplegic arrest for 4 hours at 4 degrees C. Six groups, each of 6 hearts, were studied: control; control treated with 3-aminotriazole, an inhibitor of catalase; sham; sham + 3-aminotriazole; heat-shocked rats; heat shocked rats + 3-aminotriazole. Postischemic recovery of cardiac output and endothelial function (as % of preischemic control values) were respectively 54.6 +/- 1.9 and 21.2 +/- 3.0 in the control group; 52.3 +/- 2.9 and 19.1 +/- 3.9 in the control + 3-aminotriazole group; 72.2 +/- 2.7 and 54.2 +/- 7.6 in the heat shocked group; and 68.0 +/- 4.0 and 21.0 +/- 5.8 in the heat shocked + 3-aminotriazole group. SDS PAGE and western blotting showed induction of heat shock proteins in the heat stressed animals. Measurement of catalase activity showed significant inhibition in the 3-aminotriazole treated groups. It is concluded that, following heat shock stress, the enhanced endothelial recovery after prolonged ischemic cardioplegic arrest is dependent on catalase activity but that this does not apply to the recovery of mechanical functional.

Amitrole↗