Biomedical subjects

A Aviv

Publications and source records attributed to A Aviv.

At least 19 recordsLinked to original sources

PubMed2000

Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis.

Editing of the nonprotein amino acid homocysteine by certain aminoacyl-tRNA synthetases results in the formation of the thioester homocysteine thiolactone. Here we show that in the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone. The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. Folic acid inhibits the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endothelial cells. We also show that the extent of post-translational protein homocysteinylation increases with increasing homocysteine levels but decreases with increasing folic acid and HDL levels in endothelial cell cultures. These data support a hypothesis that metabolic conversion of homocysteine to thiolactone and protein homocysteinylation by thiolactone may play a role in homocysteine-induced vascular damage.

Arteriosclerosis↗

PubMed2000

Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis.

Little is known about the turnover rate (i.e. the rate of replication and death) of cells in the intima and media of human arteries as a function of age and atherosclerosis. One indicator of the replicative history of cells is telomere length. In this work we explored the rate of telomere attrition as a function of age and atherosclerosis in cells of the human abdominal aorta. Telomere length, measured by the terminal restriction fragment using Southern analysis, was determined in the intima and media of the distal (infrarenal) versus proximal (suprarenal) segments of the abdominal aorta. Telomere length was then correlated with age and atherosclerotic grade. The rate of age-dependent telomere attrition was higher in both the intima and media of the distal versus proximal abdominal aorta. In addition, telomere length was negatively correlated with atherosclerotic grade. However, after adjustment for age, this relationship was not statistically significant. The high rate of age-dependent telomere attrition in the distal abdominal aorta probably reflects enhanced cellular turnover rate due to local factors such as an increase in shear wall stress in this vascular segment.

Adolescent↗

PubMed2000

Cellular proliferation and telomerase activity in CHRF-288-11 cells.

Telomerase activity is detected in many immortalized cell lines. Recent studies suggest that terminal differentiation of some of these cell lines is associated with a reduction in telomerase activity. However, the question remains whether the reduction in telomerase activity results from terminal differentiation or from cessation of cellular proliferation. This was explored in the megakaryocytic cell line CHRF-288-11. Cells were treated with phorbol 12-myristate 13-acetate (PMA), which induces terminal differentiation of CHRF-288-11 cells, EGTA, serum depletion, and okadaic acid. All treatments resulted in cessation of proliferation. Except for okadaic acid, these treatments also induced inhibition of telomerase within 7 days. Restoring the original growth conditions of cells treated with PMA, EGTA and serum depletion resulted in the reversal of telomerase inhibition and an acceleration of proliferation. Apparent inhibition of telomerase was observed to follow the cessation of proliferation, whereas enhanced telomerase activity was noted to precede acceleration in proliferation. Thus, telomerase activity usually reflects the proliferative status rather than the differentiated status of CHRF-288-11 cells.

Cell Division↗

PubMed2000

Telomere length inversely correlates with pulse pressure and is highly familial.

There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.

Adolescent↗

PubMed2000

Mammalian heparanase as mediator of tumor metastasis and angiogenesis.

Expression of heparan sulfate-degrading endoglycosidases, commonly referred to as heparanases, correlates with the metastatic potential of tumor cell lines, and treatment with heparanase inhibitors markedly reduces the incidence of metastasis in experimental animals. We purified a 50 kDa heparanase from human hepatoma and placenta and cloned a cDNA and gene encoding a protein of 543 amino acids. Only one heparanase sequence was identified, suggesting that this enzyme is the dominant endoglucuronidase in mammalian tissues. Expression of the cloned cDNA in insect and mammalian cells yielded 65 kDa and 50 kDa recombinant proteins. The 50 kDa enzyme represents an N-terminal processed enzyme that is at least 200-fold more active than the full-length 65 kDa form. Processing was demonstrated following incubation of the full-length recombinant enzyme with intact tumor cells. The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and in specimens of human melanomas and carcinomas. In the colon, both the heparanase mRNA and protein are expressed already at the stage of tubulovillous adenoma, but not in the adjacent 'normal-looking' colon epithelium. Non-metastatic murine T lymphoma and melanoma cells transfected with the heparanase gene acquired a highly metastatic phenotype in vivo. Apart from its involvement in the egress of cells from the vasculature, heparanase is tightly involved in angiogenesis, both directly--by promoting invasion of endothelial cells (vascular sprouting), and indirectly--by releasing heparan sulfate-bound basic fibroblast growth factor, and generating HS degradation fragments that promote bFGF activity. The angiogenic potential of heparanase was demonstrated in vivo (Matrigel plug assay) by showing a three to fourfold increase in neovascularization induced by Eb T lymphoma cells following their transfection with the heparanase gene. The ability of heparanase to promote both tumor angiogenesis and metastasis makes it a promising target for cancer therapy.

Animals↗

PubMed1999

Telomeres and essential hypertension.

The dynamics of telomere attrition in human beings might shape the course of age-dependent, complex genetic traits. One of these traits is essential hypertension. Age-dependent telomere attrition could lead to critically shortened telomeres and aneuploidy (ie, the loss or gain of chromosomes) with a resultant mosaicism that will be variably expressed in different cells and tissues. The chromosomal instability and loss of heterozygosity resulting from this process would promote an age-dependent expression of variant genes that harbor susceptibility for essential hypertension or genes that accelerate the process of aging.

Age Factors↗

PubMed1999

The relationship between Ca2+-ATPase and freely exchangeable Ca2+ in the dense tubules: a study in platelets from women.

The main aims of this work were to examine in women: the relationship between the freely exchangeable Ca2+ (FECa2+) in the dense tubules and the activity of the sarco(endo)plasmic reticulum (SER) Ca2+-ATPase (SERCA) in platelets, and the relationship of these parameters with blood pressure and serum lipoproteins. Platelets from 14 white and 13 black women in good health were studied. The FECa2+ was measured as the ionomycin-evoked Ca2+ release (in the presence of thapsigargin) in Ca2+-free medium. SERCA activity was measured as the thapsigargin sensitive, Ca2+ dependent and ouabain resistant, ATP hydrolyses in platelet membranes. Relative expressions of SERCA 2 and 3 isoforms and Ras-related protein (Rap) 1 in platelet membranes were determined by Western immunoblots. Highly significant correlations were observed for FECa2+ in the dense tubules with: 1) the maximal reaction velocity (Vmax) of the SERCA (r = 0.592, P = .0014), and 2) Rapl (r = 0.551, P = .0035). In addition, negative correlations were observed between FECa2+ in the dense tubules and age. No correlations were observed for these variables with blood pressure or serum lipoproteins. We conclude the FECa2+ and the Vmax of the SERCA are reliable indicators of Ca2+ load in platelets from women. However, in women, unlike previous observations in men, these platelet parameters are not correlated with blood pressure and serum lipoproteins.

Adult↗

PubMed1999

Physiological and molecular characterization of the Na+/Ca2+ exchanger in human platelets.

In this report, we have demonstrated that Na+/Ca2+ exchanger activity in a human megakaryocytic cell line (CHRF-288 cells) is K+ dependent, similar to the properties previously described for Na+/Ca2+ exchange activity in human platelets. With the use of RT-PCR techniques and mRNA, the exchanger expressed in CHRF-288 cells was found to be identical to that expressed in human retinal rods. Northern blot analysis of the mRNA for the human retinal rod exchanger in CHRF-288 cells revealed a major transcript at 5.8 kb with two minor bands at 4.9 and 6.8 kb. mRNA for the retinal rod exchanger was also identified in human platelets. Using Ba2+ influx as a measure of Na+/Ca2+ exchange activity in human platelets, we have demonstrated that exchange activity is driven by the transmembrane gradient for K+ as well as that for Na+. We propose that the K+ dependence of the platelet Na+/Ca2+ exchanger could make platelets especially sensitive to daily fluctuations in salt intake.

Blood Platelets↗

PubMed1998

Salt wars.

Explore the source record for details and available documents.

Calcium↗

PubMed1998

Antidepressant-associated mania: a study of anxiety disorders patients.

Antidepressants are related to the emergence of manic and hypomanic episodes in mood disorder patients. This study examined whether antidepressant-associated manic states are also present in anxiety disorder patients, so that this phenomenon may be defined as a side-effect. A total of 167 consecutive patients at a specialized outpatient clinic, suffering from anxiety disorders and treated by antidepressants, were assessed in a blind, retrospective chart review. Five patients (2.99%) were identified as having suffered an episode of antidepressant-associated mania within 3 months of initiation of treatment. All were females and all had an axis II diagnosis of a cluster B personality disorder. Antidepressant-associated mania appears to be related to risk factors such as personality disorder, even in non-mood disorder patients, tentatively suggesting that it is not simply an adverse event but rather a reflection of an underlying psychopathology.

Adult↗

PubMed1998

Synchrony in telomere length of the human fetus.

Telomere length, measured by terminal restriction fragments, was examined in tissues from human fetuses of gestational ages estimated as 15-19 weeks. The length of telomeres was similar in most fetal tissues. However, there were significant variations in telomere length among fetuses, with no apparent relationship between gestational age and telomere length. We conclude that synchrony in telomere length exists among tissues of the human fetus. This synchrony is apparently lost during extrauterine life.

Body Weights and Measures↗

PubMed1998

Telomeres, hidden mosaicism, loss of heterozygosity, and complex genetic traits.

Telomeres appear to function as an endogenous timing mechanism in human beings. Telomere attrition not only provides a satisfactory explanation for some aspects of aging, it might also resolve enigmatic features of complex genetic traits that are age-dependent. If, with the passage of time, telomere attrition in human beings leads to genomic instability and particularly the loss of chromosomes, then the age dependency of phenotypic expressions of complex genetic traits might result from the temporal loss of heterozygosity and the consequent expression of disease-causing genes. In this way, telomere attrition might play a role not only in aging, but also in the diverse expression of complex genetic traits, such as essential hypertension, non-insulin-dependent diabetes mellitus, atherosclerosis, and cancer.

Aging↗

PubMed1998

Life after infertility treatment: a long-term investigation of marital and sexual function.

After leaving in-vitro fertilization (IVF) treatment, both successful and unsuccessful women are generally lost to follow-up. In order to assess overall life satisfaction as well as marital and sexual adjustment after the completion of infertility treatment, three groups of women were studied: group 1 (n = 41), successful IVF women; group 2 (n = 16), unsuccessful IVF women who adopted; and group 3 (n = 18), unsuccessful IVF women who remained childless. All women who had completed a minimum of three IVF cycles between the years 1982 and 1993 were invited to participate in a 'life after infertility' follow-up study. Those who agreed were mailed a lengthy questionnaire which included questions about their reproductive history and infertility treatment, the impact of infertility on their marital and sexual relationship and their final thoughts about treatment. Four standardized questionnaires were also administered. Results revealed that women who became biological mothers through IVF were significantly more satisfied with their lives than women who were unsuccessful in IVF and remained childless (F = 8.62, P < 0.001). Childless women reported that infertility had exerted a significantly greater negative impact on their marriages than that reported by the other two groups. There were no significant differences, however, between the three groups on the standardized measures of marital and sexual satisfaction.

Female↗

PubMed1998

Ca2+ in the dense tubules: a model of platelet Ca2+ load.

In this work, we explored the relationship between the freely exchangeable Ca2+ (FECa2+) in the dense tubules (DT) and the sarco(endo)plasmic reticulum (SER) Ca2+-ATPase (SERCA) in circulating human platelets and examined the relationship between blood pressure (BP) and these platelet parameters. Studying platelets from 32 healthy men, we showed that the maximal reaction velocity (Vmax) of the SERCA significantly correlated with FECa2+ in the DT and with the protein expressions of SERCA 2 and 3. BP positively correlated with both the Vmax of the SERCA (r=.462, P=.010) and the FECa2+ sequestered in the DT (r=.492, P=.005). The relationships between these platelet Ca2+ parameters and BP were in part confounded by increased levels of serum triglycerides and diminished HDL cholesterol with a higher BP. No correlation was observed between the resting cytosolic Ca2+ and BP. Collectively, these findings indicate that (1) an increase in the cellular Ca2+ load in platelets is expressed by a higher activity of the SERCA and an increase in the expressions of SERCA 2 and 3 proteins, coupled with an increase in the FECa2+ in the DT, and (2) a higher BP is associated with an increase in platelet Ca2+ load in human beings, expressed by a rise in the FECa2+ in the DT and the upregulation of SERCA activity.

Adult↗

PubMed1998

Parameters of lymphocyte Na+-Ca2+ regulation and blood pressure: the gender effect.

Alterations in cellular Ca2+ and Na+ regulation play a role in the pathogenesis of essential hypertension. Using peripheral lymphocytes from 68 normal persons, we observed the following relationships for major cellular Ca2+ regulatory parameters. Among men and women, Na+-Ca2+ exchanger activity was positively correlated with the resting cytosolic free Ca2+ ([Ca2+]c) (r=0.43, P=0.0003), and the resting [Ca2+]c was positively correlated with cytosolic Na+ ([Na+]c) (r=0.50, P=0.0001). For men only, store-operated Ca2+ entry was positively correlated with Na+-Ca2+ exchanger activity (r=0.63, P=0.0001). In addition, systolic and diastolic blood pressures were positively correlated with [Na+]c in men (r=0.53, P=0.001, and r=0. 41, P=0.017, respectively) but not in women (r=0.30, P=0.088, and r=0.24, P=0.17, respectively). Some of the relationships between cellular and blood pressure parameters were confounded by serum triglycerides. These observations indicate a gender effect on cellular Ca2+-Na+ regulation and its relationship with blood pressure.

Adult↗

PubMed1998

Shortened telomere length in white blood cells of patients with IDDM.

IDDM is a polygenic and autoimmune disorder in which subsets of white blood cells (WBCs) are engaged in the destruction of beta-cells of the pancreas. The mechanisms that account for the abnormal behavior of these cells in IDDM are not fully understood. By measuring the mean length of telomeres of WBCs from patients with IDDM, we tested the concept that telomeres might play a role in IDDM. We examined the lengths of the terminal restriction fragments (TRFs) of DNA of WBCs from 234 white men comprising 54 patients with IDDM, 74 patients with NIDDM, and 106 control subjects. When adjusted for age, the TRF length from WBCs of patients with IDDM was significantly shorter than that of nondiabetic control subjects (mean +/- SE: 8.6 +/- 0.1 vs. 9.2 +/- 0.1, P = 0.002). No significant difference was observed between the TRF length from WBCs of patients with NIDDM versus nondiabetic subjects. Neither the duration nor the complications of IDDM (i.e., nephropathy and hypertension) had an effect on the TRF length of WBCs from patients with IDDM. The shortened TRF length of WBCs of patients with IDDM likely reflects a marked reduction in the TRF length of subsets of WBCs that play a role in the pathogenesis of IDDM.

Adolescent↗

PubMed1997

Oligomycin inhibits store-operated channels by a mechanism independent of its effects on mitochondrial ATP.

Inhibitors of mitochondrial oxidative metabolism have been proposed to interfere with Ca2+ influx mediated by store-operated channels (SOC), secondary to their effects on ATP production. We assessed SOC activity by 45Ca2+ influx and fluorimetric measurements of free Ca2+ or Mn2+ quench in thapsigargin-treated Chinese hamster ovary cells and Jurkat T-cells, and additionally by electrophysiological measurements of the Ca2+-release-activated Ca2+ current (Icrac) in Jurkat T-cells. Various mitochondrial antagonists were confirmed to inhibit SOC. However, the following evidence supported the proposal that oligomycin, in particular, exerts an inhibitory effect on SOC in addition to its known actions on mitochondria and Na+-pump activity: (i) the concentrations of oligomycin required to inhibit SOC-mediated Ca2+ influx or Icrac (half-inhibitory concentration approximately 2 microM) were nearly 50-fold higher than the concentrations that blocked mitochondrial ATP production; (ii) the rank order of potency of oligomycins A, B and C for decreasing SOC-mediated Ca2+ influx or Icrac differed from that known for inhibition of mitochondrial function; (iii) oligomycin blocked Icrac under voltage clamp and with intracellular Na+ and K+ concentrations fixed by dialysis from the patch pipette, arguing that the effect was not secondary to membrane polarization or pump activity; and (iv) fixing the cytosolic ATP concentration by dialysis from the patch pipette attenuated rotenone- but not oligomycin-mediated inhibition of Icrac. Oligomycin also blocked volume-activated Cl- currents, a profile common to some other known blockers of SOC that are not known mitochondrial inhibitors. These findings raise the possibility that oligomycin interacts directly with SOC, and thus may extend the known pharmacological profile for this type of Ca2+-influx pathway.

Adenosine Triphosphate↗

PubMed1997

Lack of difference in oxalate-dependent Ca2+ uptake by membrane homogenate of African-American and white subjects.

In order to further characterize previously described racial differences in intracellular Ca2+ homeostasis, the activity of sarcoplasmic-endoplasmic reticulum Ca2+-ATPase was measured in cultured skin fibroblasts from normotensive African-Americans and whites. Cells originated from apparently healthy, normotensive African-American (n = 15) and white (n = 15) subjects. The activity of the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase was measured by: 1) oxalate-dependent only, and 2) oxalate-dependent, thapsigargin-sensitive 45Ca2+ uptake of membrane homogenates. Over 90% of the oxalate-dependent 45Ca2+ uptake was thapsigargin-sensitive. There was no detectable racial difference in the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase activity with either technique. It is concluded that the previously described higher cellular Ca2+ turnover and larger cellular stores of exchangeable Ca2+ in cells from African-Americans versus whites are not due to changes in the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase itself. The findings do not exclude possible increased activity of this enzyme in intact cells of African-Americans where regulatory mechanisms not present in the membrane preparation may operate.

Black People↗