Biomedical subjects

I J Benjamin

Publications and source records attributed to I J Benjamin.

24 records · Page 2Linked to original sources

PubMed1992

beta Adrenergic receptor desensitisation may serve a cardioprotective role.

OBJECTIVE: The aim was to test the hypothesis that beta adrenoceptor desensitisation is a form of cardioprotection whereby the myocardium is protected from the injurious effects of excessive adrenergic stimulation by isoprenaline. METHODS: A new sensitive and specific method of identifying cardiac myocyte necrosis with monoclonal antimyosin was employed. Antibody labelled necrotic cardiomyocytes from male Sprague-Dawley rats (190-300 g) were identified by immunofluorescence. Homologous beta adrenoceptor desensitisation was induced by 9 d pretreatment with isoprenaline infusion (20 mg.kg-1.d-1), and heterologous desensitisation by treatment with 0.15% propylthiouracil in the diet for six weeks. The effects of isoprenaline induced cardiomyocyte injury in these animals were compared with those in control rats. RESULTS: In euthyroid control rats, treatment with the beta adrenergic agonist, isoprenaline, produced prolonged tachycardia and hypotension, and a significant amount of cardiac myocyte necrosis subendocardially. When the same isoprenaline challenge was given to rats pretreated for 9 d with an isoprenaline infusion, the haemodynamic response was markedly attenuated and very little myocyte necrosis was noted. In the model of heterologous desensitisation occurring in hypothyroidism, isoprenaline challenge produced markedly diminished haemodynamic response and little cardiac myocyte necrosis. CONCLUSIONS: In both homologous and heterologous models of beta adrenoceptor desensitisation, the susceptibility of the myocardium to isoprenaline induced cytotoxicity is markedly reduced.

Adrenergic beta-Antagonists↗

PubMed1992

Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia.

Expression of major stress proteins is induced rapidly in ischemic tissues, a response that may protect cells from ischemic injury. We have shown previously that transcriptional induction of heat-shock protein 70 by hypoxia results from activation of DNA binding of a preexisting, but inactive, pool of heat shock factor (HSF). To determine the intracellular signals generated in hypoxic or ischemic cells that trigger HSF activation, we examined the effects of glucose deprivation and the metabolic inhibitor rotenone on DNA-binding activity of HSF in cultured C2 myogenic cells grown under normoxic conditions. Whole-cell extracts were examined in gel mobility shift assays using a 39-bp synthetic oligonucleotide containing a consensus heat-shock element as probe. ATP pools were determined by high-pressure liquid chromatography and intracellular pH (pHi) was measured using a fluorescent indicator. Glucose deprivation alone reduced the cellular ATP pool to 50% of control levels but failed to activate HSF. However, 2 x 10(-4) M rotenone induced DNA binding of HSF within 30 min, in association with a fall in ATP to 30% of control levels, and a fall in pHi from 7.3 to 6.9. Maneuvers (sodium propionate and amiloride) that lowered pHi to 6.7 without ATP depletion failed to activate HSF. Conversely, in studies that lowered ATP stores at normal pH (high K+/nigericin) we found induction of HSF-DNA binding activity. Our data indicate that the effects of ATP depletion alone are sufficient to induce the DNA binding of HSF when oxidative metabolism is impaired, and are consistent with a model proposed recently for transcriptional regulation of stress protein genes during ischemia.

Acidosis↗

PubMed1991

Stress proteins and cardiovascular disease.

Understanding the molecular basis by which cells of the heart and blood vessels adapt to physiological stress conditions is an important goal for cardiovascular investigators. The ubiquitous heat shock response provides a model for cellular adaptations to metabolic stresses that are encountered in cardiac disease. Stress-induced synthesis of a family of highly conserved proteins serves to protect cells from injury. In addition, members of this family have essential roles in protein processing and assembly of macromolecular complexes, and in regulation of gene expression, even in unstressed cells. Research concerning the regulation and function of stress proteins potentially is pertinent to the pathophysiology of myocardial hypertrophy, remodeling, and failure, to age-related changes in the cardiovascular system, as well as to ischemic heart disease.

Animals↗

PubMed1990

Activation of the heat shock transcription factor by hypoxia in mammalian cells.

Members of the stress protein family such as HSP70 are induced in ischemic tissues and may contribute to the ability of cells to survive episodes of transient circulatory insufficiency. However, the biochemical events that lead to this induction, and their degree of similarity with pathways triggered by heat stress, have not been defined. In this study, we demonstrate that transient exposure of cultured C2C12 mouse myogenic cells to a hypoxic atmosphere stimulates DNA binding activity of the heat shock transcription factor through mechanisms that are independent of new protein synthesis. Activation of heat shock transcription factor in hypoxic cells is temporally associated with induction of endogenous HSP70 gene transcription and with induction of a heterologous reporter gene controlled by the human HSP70 promoter. Furthermore, induction of the human HSP70 promoter by hypoxia requires an intact heat shock element, indicating that other cis-acting transcriptional control elements contained within this complex promoter are not sufficient to transduce signals generated within hypoxic cells. These findings provide strong evidence that hypoxia and heat shock induce expression of the HSP70 gene by similar, if not identical, mechanisms.

Anaerobiosis↗

PubMed1989

Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis.

Treatment of rats with the beta-adrenergic agonist isoproterenol results in cardiac hypertrophy, myocyte necrosis, and interstitial cell fibrosis. Our objectives in this study have been to examine whether hypertrophy and fibrosis occur in a compensatory and reparative response to myocyte loss or whether either process may be occurring independently of myocyte loss and thus be a reactive response to adrenergic hormone stimulation. We have examined this question by evaluating each of these responses in rats treated with different doses and forms of isoproterenol administration. Myocyte necrosis was evaluated using in vivo labeling with monoclonal antimyosin for identification of myocytes with permeable sarcolemma, which was indicative of irreversible injury. Myocardial fibrosis was evaluated by morphometric point counting of Gomori-stained tissue sections and by assessment of the stimulation of fibroblast proliferation by determination of increased levels of DNA synthesis. Stimulation of fibroblast DNA synthesis was determined from DNA specific radioactivities and radioautography after pulse labeling with [3H]thymidine. The evidence provided by this study suggests that the degree and timing of myocardial hypertrophy does not follow the course of myocyte loss and, thus, appears to be either a response to altered cardiac loading or a reactive response to beta-adrenergic hormone stimulation rather than a compensation for myocyte loss. Myocardial fibrosis, on the other hand, appears to be more closely related to myocyte necrosis with respect to collagen accumulation in the same areas of the heart, its dose-response relation to the amount of isoproterenol administered, and the timing of increased DNA synthesis, or fibroblast proliferation, after myocyte loss.

Animals↗

PubMed1981

Cardiac hypertrophy in idiopathic dilated congestive cardiomyopathy: a clinicopathologic study.

Although clinical studies indicate that patients with idiopathic dilated congestive cardiomyopathy who develop electrocardiographic or angiographic signs of left ventricular (LV) hypertrophy may survive longer, there is little morphologic evidence for such anatomic favorable of unfavorable prognostic groups. We studied 30 autopsied patients who died of dilated cardiomyopathy; of these, 15 died within 1 year of the first symptom of their disease (short-term survivors) and 15 patients died 1-14 years after initial symptoms (long-term survivors). There were no significant differences in sex, race, clinical presentation or cause of death between the groups, but there were significant morphologic differences. In the short-term survivors, average heart weight was 540 g and LV wall thickness was 1.0 cm, whereas in the long-term survivors, the average heart weight was 759 g and LV wall thickness was 1.3 cm (p less than 0.001). LV cavity dilatation as measured by maximal transverse diameter from the postmortem angiograms did not differ between the two groups. These patients were compared with 10 autopsied patients with normal hearts and no clinical cardiac disease and 10 autopsied patients with volume overload secondary to valvular regurgitation. An LV hypertrophy/dilatation index (thickness/diameter) was 0.17 +/- 0.07 for the short-term survivors, 0.21 +/- 0.07 for the long-term survivors, 0.38 +/- 0.07 for volume overload patients, and 0.48 +/- 0.19 for normal subjects (F = 20.24, p less than 0.001). Thus, in patients with hypertrophy due to volume overload, wall thickening increased with dilatation, returning the ratio of wall thickness to cavity size toward normal. In contrast, among the idiopathic congestive cardiomyopathies, dilatation was disproportionate to hypertrophy and the difference was most marked for short-term survivors.

Adult↗