ABSTRACT
Enhanced cell survival and resistance to apoptosis during thermotolerance correlates with an increased expression of heat shock proteins (Hsps). Here we present additional evidence in support of the hypothesis that the induction of Hsp27 and Hsp72 during acquired thermotolerance in Jurkat T-lymphocytes prevents apoptosis. In thermotolerant cells, Hsp27 was shown to associate with the mitochondrial fraction, and inhibition of Hsp27 induction during thermotolerance in cells transfected with hsp27 antisense potentiated mitochondrial cytochrome c release after exposure to various apoptotic stimuli, despite the presence of elevated levels of Hsp72. Caspase activation and apoptosis were inhibited under these conditions. In vitro studies revealed that recombinant Hsp72 more efficiently blocked cytochrome c-mediated caspase activation than did recombinant Hsp27. A model is presented for the inhibition of apoptosis during thermotolerance in which Hsp27 preferentially blocks mitochondrial cytochrome c release, whereas Hsp72 interferes with apoptosomal caspase activation.
Subject(s)
Apoptosis/physiology , Heat-Shock Proteins/metabolism , Heat-Shock Response/physiology , Jurkat Cells/cytology , Mitochondria/metabolism , Caspase 3 , Caspase 9 , Caspases/metabolism , Cytochrome c Group/metabolism , Cytosol/metabolism , Enzyme Precursors/metabolism , Humans , Jurkat Cells/enzymologyABSTRACT
BACKGROUND AND OBJECTIVES: Atherosclerosis is a multifactorial disease, in part characterized by chronic inflammatory changes in the vessel wall and loss of normal physical and biochemical interactions between endothelial cells and smooth muscle cells. Previous studies [Hu J., Cotgreave IA. J Clin Invest; 99: 1-5] have provided molecular links between inflammation and myoendothelial communication via gap junctions, suggesting that these structures may be important in the development of the atherosclerotic vessel phenotype. In order to strengthen this premise, the aim of the present work was to probe for structural polymorphisms in connexin 37, a gap junctional protein uniquely expressed in endothelial cells, and to assess for potential genotypic segregation in individuals displaying atherosclerotic plaque. METHODS AND RESULTS: Computer-based comparisons of Expressed Sequence Tags (ESTs) predicted a polymorphism in the human gap junctional protein connexin 37 (cx37). The C1019-T mutation results in a proline to serine shift at codon 319 (cx37*1-cx37*2). A Restriction Fragment Length Polymorphism (RFLP) assay, involving the insertion of a novel Drd I cleavage site in the proline variant revealed a statistically significant over-representation of the cx37*1 allele in association with atherosclerotic plaque-bearing individuals (Odds-ratio for the homozygote = 2.38, Chi2 = 7.693, P = 0.006), in comparison to individuals lacking plaque, irrespective of a history of hypertension. CONCLUSIONS: These data suggest that the C1019-T polymorphism in cx37 may provide 'single gene marker', which could be useful in assessing atherosclerotic plaque development, particularly in cardiovascular risk groups such as those with borderline hypertension.
Subject(s)
Arteriosclerosis/genetics , Biomarkers , Connexins/genetics , Polymorphism, Genetic , Adult , Alleles , Carotid Stenosis/genetics , Case-Control Studies , DNA Primers , Female , Humans , Male , Middle Aged , Polymorphism, Restriction Fragment Length , Prognosis , Sequence Analysis, DNA , Sweden , Up-Regulation , Gap Junction alpha-4 ProteinABSTRACT
The difference in the hearing threshold before and after treatment with cis-diaminnedichloroplatinum (DDP) is analysed in 69 patients. Hearing loss due to DDP treatment is mainly limited to 8,000 Hz and the incidence is about 40%. The effect of DDP is dose-related, although even at the lowest dose 20% of the patients are affected. The age of the patients is not an important factor. Loss of hearing due to DDP treatment occurs independent of any pre-existent hearing loss although those patients with great pre-existent hearing loss do not show a further loss. Of the patients with hearing loss, 39% show a difference of 20 dB or more between the left and the right ear. Hearing loss due to DDP is of minor importance compared with many of the other side-effects of DDP.
Subject(s)
Cisplatin/adverse effects , Hearing Loss, High-Frequency/chemically induced , Hearing Loss/chemically induced , Auditory Threshold , Dose-Response Relationship, Drug , Female , HumansABSTRACT
Gentamicin-induced cochlear degeneration in the guinea pig was studied by complete hair-cell counting (cytocochleograms) and phase-contrast and interference microscopical examination of the stria vascularis and Reissner's membrane. Gentamicin (100 mg/kg/day) was administered over a period of 7-17 days. The first loss of hair cells (OHC) occurred in a region 6-8 mm from the round window. From this 'degeneration point', the loss of haircells progressed towards the round window (fast) and the apex (slowly). The stria vascularis showed no signs of degeneration. Reissner's membrane, on the other hand, showed intracellular vacuolization of the endolymphatic cells over the complete length of the cochlea after 12 or more days intoxication. Hearing loss was measured by electrocochleography with skin electrodes. The histologic findings were compared with the objective audiograms.
