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Biomedical subjects

J D Wagner

Publications and source records attributed to J D Wagner.

At least 55 records · Page 3Linked to original sources
PubMed1998

Sonchus yellow net rhabdovirus nuclear viroplasms contain polymerase-associated proteins.

We have initiated a study of the cytopathology of nucleorhabdoviruses by analyzing the subcellular localization of sonchus yellow net virus (SYNV) genomic and antigenomic RNAs and the encoded polymerase proteins. In situ hybridizations demonstrated that the minus-strand genomic RNA sequences are restricted to the nuclei of infected cells, while the complementary plus-strand antigenomic RNA sequences are present in both the nuclei and the cytoplasm. Immunofluorescence and immunogold labeling experiments also revealed that the nucleocapsid (N) protein and phosphoprotein (M2) are primarily localized to discrete regions within the nuclei and in virus particles that accumulate in perinuclear spaces. The N protein antiserum specifically labeled the nuclear viroplasms, whereas the M2 antiserum was more generally distributed throughout the nuclei. Antibody detection also indicated that the polymerase (L) protein is present in small amounts in the viroplasm. When the N and M2 proteins were expressed individually from the heterologous potato virus X (PVX) vector, both proteins preferentially accumulated in the nuclei. In addition, viroplasm-like inclusions formed in the nuclei of cells infected with the PVX vector containing the N gene. Fusions of the carboxy terminus of beta-glucuronidase to N and M2 resulted in staining of the nuclei of infected cells following expression from the PVX vector. Deletion analyses suggested that multiple regions of the N protein contain signals that are important for nuclear localization.

Cell Nucleus↗
PubMed1998

Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with estradiol alone or combined with nomegestrol acetate.

We have previously shown that medroxyprogesterone acetate (MPA), either alone or combined with conjugated equine estrogens (CEE), significantly decreased insulin sensitivity (SI), compared with both untreated controls and those treated with CEE alone. The purpose of this study was to determine the effects of estradiol (E2), with and without nomegestrol acetate (NA; a potent progestin that lacks androgenic activity), on SI and arterial antioxidant activity, as determined by F2-isoprostanes. Thirty-six adult female cynomolgus monkeys (Macaca fascicularis) were ovariectomized and fed a moderately atherogenic diet, with one of the following three treatments added to the diet, for 12 weeks: 1) no treatment (control); 2) E2; or 3) continuous combined E2 + NA (E2+NA). SI and glucose effectiveness were assessed by the frequently sampled i.v. glucose tolerance test using a third-phase insulin infusion after 10 weeks of treatment. Cholesterol content and F2-isoprostanes were measured in the thoracic aorta after 12 weeks of treatment. E2 treatment resulted in a significantly greater SI, compared with control or E2+NA-treated monkeys (10.03 +/- 0.91 vs. 6.35 and 6.49 x 10(-4) min(-1) microU(-1) mL; P < 0.05). In contrast to our studies of CEE and MPA, E2+NA treatment, though reducing the SI below that of the E2 group, did not reduce the SI below that of control monkeys. As expected, the short period of treatment resulted in no significant differences in aortic cholesterol content. There was no treatment effect on total F2-isoprostanes (representing F2-isoprostane formation caused primarily by autooxidation), suggesting minimal antioxidant activity. However, there was a treatment difference in the prostaglandin F2alpha (PGF2alpha) isomer (a prostaglandin (PG) isomer formed by both autooxidation of arachidonate and cyclooxygenase activity). PGF2alpha concentrations were 32% lower with E2 treatment, compared with controls, and 36% lower, compared with E2+NA treatment (0.48 +/- 0.08 vs. 0.71 +/- 0.12 and 0.75 +/- 0.06; P < 0.05), suggesting differences in PG synthesis between hormone treatments. In conclusion, NA, a progestin without androgenic activity, may still affect some cardiovascular risk factors differently than estrogen-only therapy. However, it seems to be less detrimental than MPA.

Administration, Oral↗
PubMed1998

Streptozotocin-induced diabetes mellitus in cynomolgus monkeys: changes in carbohydrate metabolism, skin glycation, and pancreatic islets.

Chronic hyperglycemia has been implicated in a number of diabetes mellitus-related conditions in the human population, including retinopathy, neuropathy, nephropathy, and vasculopathy. However, it has been difficult to evaluate the effect of long-term hyperglycemia in a research setting because of the disease's slow progression. In this study, we used streptozotocin (30 mg/kg of body weight, intravenously) to induce a state of chronic hyperglycemia in eight cynomolgus monkeys, and compared these monkeys with a matched control group (n = 8). Seven of eight monkeys with streptozotocin-induced diabetes required insulin therapy to avoid ketosis. After disease induction, all diabetic monkeys had significantly higher preprandial plasma glucose and glycated hemoglobin values, compared with their baseline values or values for control monkeys. Diabetic monkeys also had abnormal responses to an intravenous glucose tolerance test. Consistent with the chronic hyperglycemic state and formation of advanced glycation end products, diabetic monkeys had a significant increase in skin fluorescence over the course of the 6-month study. Plasma triglyceride and cholesterol concentrations increased, but not significantly so, in the diabetic monkeys after disease induction and were not significantly different from concentrations in control monkeys. Six months after disease induction, monkeys were necropsied, and immunohistochemical staining for insulin in the pancreatic islets indicated that diabetic monkeys had a significantly decreased amount of staining for the hormone. The percentage of islet insulin staining was significantly correlated with physiologic responses to the postinduction intravenous glucose tolerance test in all monkeys. Because cynomolgus monkeys are well-characterized models of atherosclerosis, this model may be useful for determining mechanisms whereby diabetes mellitus increases cardiovascular disease.

Animals↗
PubMed1998

Simulated glomerular hypertension promotes mesangial cell apoptosis and expression of cathepsin-B and SGP-2.

BACKGROUND: Focal glomerulosclerosis (FGS) is characterized by the accumulation of mesangial matrix and lack of mesangial cells (MC). We studied the role of glomerular hypertension (GH) in the development of MC hypoplasia. METHODS: We used an in vitro model of GH to study the effect of GH on MC apoptosis. Cultured rat endothelial cells were grown in the intracapillary space and MCs were grown in the extracapillary space. MC proliferation as well as apoptosis was evaluated under simulated normal glomerular pressure (SNGP) as well as simulated glomerular hypertension (SGH). Apoptosis was determined morphologically by DNA fragmentation using Hoechst staining as well as with the use of DNA gel electrophoresis. MCs grown under SNGP and SGH were also evaluated for the expression of genes associated with active cell death. In addition, we evaluated the effect of direct applied pressure on MC apoptosis. RESULTS: MCs grown under SGH were less elliptical and had a tendency to develop a dome in the center. Direct applied pressure promoted MC apoptosis in a dose and time dependent manner. DNA gel electrophoresis from MCs grown under SGH also showed integer multiples of 180 base pairs (ladder pattern); whereas cells grown under SNGP showed no DNA fragmentation. SGH increased mRNA expression of cathepsin-B (SNGP, 0.31 +/- 0.04 vs SGH, 0.57 +/- 0.03, P < 0.01, n = 3) and SGP-2 (SNGP, 0.55 +/- 0.05 vs SHG, 1.08 +/- 0.12, P < 0.01, n = 3) in MCs when compared to cells grown under SNGP. CONCLUSIONS: The present in vitro study suggests that GH has the potential to convert a hypercellular mesangium into a hypocellular one. This effect of GH is associated with expression of genes associated with active cell death.

Animals↗
PubMed1997

Initial assessment of positron emission tomography for detection of nonpalpable regional lymphatic metastases in melanoma.

BACKGROUND: The purpose of this pilot study is to determine the feasibility of positron emission tomography with fluorodeoxyglucose (FDG-PET) for detection of nonpalpable regional lymph node metastases in patients with melanoma. METHODS: Adult patients with histologically proven cutaneous melanoma planned to undergo surgical lymphadenectomy for treatment of nonpalpable subclinical or residual metastatic melanoma in regional lymph node basin(s) participated. Each patient underwent attenuation-corrected PET imaging of the regional lymph node basin(s) with F18 fluorodeoxyglucose (FDG) followed by complete surgical lymphadenectomy. FDG-PET scans were interpreted prospectively by an experienced nuclear medicine physician. FDG-PET scan interpretations and histologic results were then correlated. RESULTS: Eleven patients underwent 12 FDG-PET scans followed by 12 operations to clear 14 regional lymph node basins. FDG-PET correctly predicted the presence of metastatic melanoma in seven of seven surgical specimens. FDG-PET scans correctly predicted the absence of disease in seven of seven histologically negative node basins. Sensitivity was 1.0; specificity was 1.0. CONCLUSIONS: This study suggests that increased fluorodeoxyglucose uptake in palpably unremarkable regional lymph node basins in patients with melanoma is highly suggestive of metastatic disease.

Adult↗
PubMed1997

Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys.

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 x 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17 beta-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction (P = .001) in aortic cholesteryl ester content. A similar trend (P = .14) was found for soy protein compared with casein. There also was a significant interaction (P = .02) with soy and E2, such that animals consuming soy protein +E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Aging↗
PubMed1997

The tensor fascia lata free flap in abdominal-wall reconstruction.

The pedicled tensor fascia lata flap (TFL flap) is a method of choice for abdominal-wall reconstruction. Frequently, the size and location of the defect produce this option. Microsurgical transfer may overcome these disadvantages. Therefore, the ability of the TFL free flap to reconstruct complex abdominal wounds was evaluated. Seven patients with full-thickness abdominal-wall defects reconstructed by TFL free flaps were reviewed. Their average age was 44.6 years (range: 27 years to 59 years); follow-up averaged 10.5 months (range: 2 months to 18 months). Fifty-seven percent of the wounds were either infected or contaminated; the defect averaged 15 cm x 26 cm Six 85.7 percent) of the wounds involved the epigastrum. No total flap loss was seen, but three flaps developed distal tip necrosis (42.9%). Microsurgical transfer of the TFL free flap overcomes the limitations of the arc of rotation seen with the pedicled flap. It increases the vascularity of the distal portion of the flap. The TFL free flap is therefore an option in abdominal wounds, particularly those with defects of large size or supraumbilical location.

Abdominal Injuries↗
PubMed1997

A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research.

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.

Aging↗
PubMed1997

Reversible hemiplegia as a consequence of severe hyperkalemia and cocaine abuse in a hemodialysis patient.

Severe hyperkalemia may cause weakness that typically is ascending and symmetric. In an isolated case report, hemiplegia occurred after the development of hyperkalemia in a patient with a known central nervous system lesion. We describe a patient requiring long-term hemodialysis who had near-fatal hyperkalemia, hemiplegia, and rhabdomyolysis after abuse of crack cocaine. The hemiplegia resolved after normalization of serum potassium using emergency dialysis. No brain lesion could be identified during computed tomography or by electroencephalography, and the patient had no residual neurologic deficits. We conclude that this patient had hemiplegia secondary to cocaine-induced cerebral vasoconstriction because no structural lesion could be found and that the neurologic deficit was worsened by severe hyperkalemia, which probably resulted from cocaine-induced rhabdomyolysis. Hence, despite the absence of a structural lesion of the brain, severe hyperkalemia, typically associated with symmetric, ascending muscle weakness, may contribute to causing focal weakness in the condition of cocaine-induced vasoconstriction.

Adult↗
PubMed1997

Characterization of the components and activity of Sonchus yellow net rhabdovirus polymerase.

Sonchus yellow net virus (SYNV) is the best-characterized member of a group of plant rhabdoviruses that replicate in the host cell nucleus. Using a recently developed method for partial purification of active SYNV polymerase by salt extraction of nuclei from infected plant tissue (J. D. O. Wagner et al, J. Virol. 70:468-477, 1996), we have identified the nucleocapsid (N), M2, and L proteins as polymerase complex components (based on copurification with the polymerase activity and by coimmunoprecipitation assays). Furthermore, the L protein was shown by antibody inhibition analysis to be a functional component of the polymerase. A second complex of M2 and L proteins, thought to be a precursor to the polymerase complex, was also identified. In addition, we conducted a detailed characterization of SYNV RNA synthesis in vitro. The results demonstrate that the RNAs are transcribed sequentially, beginning with the N mRNA and followed successively by the remaining five mRNAs in the order of their genome organization. Gene expression conforms to a cascade pattern, with synthesis of the 3'-proximal N mRNA occurring at the highest level, followed by consecutively lower levels of transcription from each subsequent gene. The reaction conditions favor transcription over minus-sense RNA replication, which, we posit, is inhibited near specific signal sequences located on the antigenomic template. The results support the concept that the mechanism of transcription is highly conserved among diverse rhabdoviruses and are compatible with a unified model for the regulation of genomic and antigenomic RNA synthesis.

Antibodies, Viral↗
PubMed1997

Effect of morphine on renomedullary interstitial cell proliferation and matrix accumulation.

Renal interstitial scarring is an important feature of heroin-associated nephropathy. We studied the effect of morphine, an active metabolite of heroin, on cultured rat renal medullary interstitial cell (RMIC) proliferation and matrix accumulation. Morphine (10(-12) M) enhanced (p < 0.001) the proliferation of RMIC (control, 15.0+/-0.5 vs. morphine, 20.4+/-1.1 x 10(4) cells/ml). This effect of morphine was dose and time dependent. [3H]thymidine and bromodeoxyuridine incorporation studies confirmed the mitogenic effect of morphine on RMIC. Morphine also enhanced mRNA expression for c-jun and c-myc on RMIC. However, nalbuphine, a non-addicting alkaloid did not modulate the proliferation of RMIC. Morphine enhanced the accumulation of collagen type I in a dose-dependent manner and also increased (p < 0.001) the accumulation of collagen type III at a high concentration (control, 1,291+/-55.8 vs. morphine, 10(-4) M, 2,697.6+/-257.8 ng/microg protein). Morphine did not modulate the accumulation of laminin or fibronectin. Neutralizing antibody to IL-6 inhibited the effect of morphine on RMIC. H7, a protein kinase C inhibitor, also attenuated the morphine-induced RMIC proliferation. The present study provides a basis for a hypothesis that morphine may be playing a role in the development of renal interstitial pathology in patients with heroin addiction.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.

Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.

Administration, Oral↗
PubMed1997

Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys.

Soy protein, long recognized as having cardiovascular benefits, is a rich source of phytoestrogens (isoflavones). To distinguish the relative contributions of the protein moiety versus the alcohol-extractable phytoestrogens for cardiovascular protection, we studied young male cynomolgus macaques fed a moderately atherogenic diet and randomly assigned to three groups. The groups differed only in the source of dietary protein, which was either casein/lactalbumin (casein, n = 27), soy protein with the phytoestrogens intact (soy+, n = 27), or soy protein with the phytoestrogens mostly extracted (soy-, n = 28). The diets were fed for 14 months. Animals fed soy+ had significantly lower total and LDL plus VLDL cholesterol concentrations compared with the other two groups. They soy+ animals had the highest HDL cholesterol concentrations, the casein group had the lowest, and the soy- group was intermediate. A subset was necropsied for atherosclerosis evaluations (n = 11 per group). Morphometric and angiochemical measures were done to quantify atherosclerosis. Coronary artery atherosclerotic lesions were smallest in the soy+ group (90% less coronary atherosclerosis than the casein group and 50% less than the soy- group), largest in the casein group, and intermediate in the soy- group. The effects of the diets on lesion size and arterial lipid measures of the peripheral arteries were similar to those in the coronary arteries, with greatest prevention of atherogenesis with soy+ and intermediate benefit with soy- relative to casein. We could not determine whether the beneficial effects seen in the soy- group relate to the protein itself or to the remaining traces of phytoestrogens. The beneficial effects of soy protein on atherosclerosis appear to be mediated primarily by the phytoestrogen component. Testicular weights were unaffected by the phytoestrogens.

Animal Feed↗
PubMed1997

Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys.

Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women and inhibits progression of coronary artery atherosclerosis in monkeys. Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties. Its antagonist activity is useful in chemotherapy of breast cancer and may have protective effects on plasma lipid concentrations, but its effects on atherogenesis have not been defined. The goal of this study was to examine the effect of tamoxifen on plasma lipids, arterial and hepatic LDL metabolism, and progression of coronary artery atherosclerosis in surgically postmenopausal female monkeys. Thirty-five monkeys were fed an atherogenic diet containing 1.3 mg.kg-1.d-1 tamoxifen (equivalent to the usual dose of 20 mg/d given to women). Thirty-one monkeys were fed the same atherogenic diet with no tamoxifen. Ten monkeys from each treatment group were fed the test diets for 12 weeks to examine the short-term effects of tamoxifen on arterial LDL metabolism. The rest of the monkeys were fed the test diets for 3 years to study the long-term effects of tamoxifen on development of atherosclerosis. In the short term, tamoxifen inhibited the rate of arterial accumulation of LDL degradation products overall (P = .03) and decreased hepatic cholesterol content (P = .003). In the long term, tamoxifen increased plasma concentrations of triglycerides (0.60 +/- 0.67 versus 0.23 +/- 0.02 mmol/L, P = .001) and reduced average LDL molecular weight (5.3 +/- 0.2 versus 4.8 +/- 0.1 g/mumol, P = 0.004) but had no effects on plasma total, LDL, or HDL cholesterol concentrations. Coronary artery atherosclerosis (intimal area, mean +/- SEM) was 0.25 +/- 0.06 mm2 in control monkeys and 0.12 +/- 0.03 mm2 in tamoxifen-treated monkeys (P = .057). We conclude that tamoxifen has antiatherogenic effects that may be modulated in part through direct effects on arterial LDL metabolism.

Animals↗
PubMed1997

Effects of short-term hormone replacement therapies on low-density lipoprotein metabolism in cynomologus monkeys.

Estrogen replacement therapy reduces the risk of coronary heart disease in women and decreases the extent of atherosclerosis in monkeys. In our previous studies, estrogen treatment decreased arterial LDL degradation and accumulation, thus indicating one mechanism by which estrogen inhibits the progression of atherosclerosis. The influence of progestins on these processes remains nuclear. The objective of this study was to determine the effects of oral estrogen (conjugated equine estrogens) and progestin (medroxyprogesterone acetate) alone or in combination on arterial LDL metabolism after 12 weeks of atherogenic stimulus. This relatively short period of treatment was chosen to determine effects on arterial LDL metabolism before substantial subendothelial macrophage accumulation. In contrast to previous studies (16 to 18 weeks of treatment), when macrophages were present in the intima, neither estrogen nor progestin (nor their combination) had any effect on any index of arterial LDL metabolism. These results suggest that estrogen may preferentially reduce LDL metabolism in macrophages with little effect on cells of the normal artery. In contrast to arterial LDL metabolism, hepatic LDL uptake was significantly increased in animals treated with estrogen or estrogen plus progestin. Despite the increased LDL uptake by the liver, hepatic lipid content was significantly decreased by approximately 50% in both estrogen and estrogen-plus-progestin treatment compared with control and progestin-treated animals. The decrease in hepatic cholesterol content in hypothesized to be due to increased biliary secretion of cholesterol.

Animals↗
PubMed1997

Effects of contraceptive estrogen and progestin on the atherogenic potential of plasma LDLs in cynomolgus monkeys.

This study was designed to determine the effect of oral contraceptive treatment (estrogen and progestin), alone or in combination, on LDL composition and atherogenic potential in cynomolgus monkeys fed an atherogenic diet. Groups (n = 8 each) of monkeys were untreated (control) or treated with ethinyl estradiol (EE), levonorgestrel (LNG); or triphasic oral contraceptive (EE+LNG) for 1.5 years before plasma LDLs were isolated for characterization. Total plasma cholesterol concentrations were unaffected by the treatments. LDL particle size (measured as LDL molecular weight, g/mumol) was significantly smaller, in the EE (4.61 +/- 0.09) and EE+LNG (4.43 +/- 0.09) treatment groups compared with the control (4.99 +/- 0.09) or LNG (5.29 +/- 0.17) groups and contained fewer molecules of free and esterified cholesterol. Both the EE and EE+LNG groups had significantly less cholesterol and apolipoprotein B distributed in the d = 1.015 to 1.025 g/mL subfraction and correspondingly more in the d = 1.025 to 1.035 g/mL subfraction of LDL compared with the control and LNG groups. The apolipoprotein E content (molecules/particle) of LDL was significantly less in the EE (0.35 +/- 0.1) and EE+LNG (0.28 +/- 0.1) groups compared with the control (0.86 +/- 0.2) and LNG (0.99 +/- 0.2) groups, and this trend was apparent in all three LDL subfractions. The atherogenic potential of LDL was tested using an in vitro binding assay to arterial proteoglycans. Twice as much LDL bound to arterial proteoglycans in the LNG group (11.3 +/- 1.8% of total LDL cholesterol in the incubation) compared with the control (6.4 +/- 1.9%), EE (5.5 +/- 1.5%), or EE+LNG (5.2 +/- 1.2%) groups. We conclude that EE and EE+LNG treatment alters the composition of LDL toward a less atherogenic particle that is smaller and more dense, contains less cholesterol and less apolipoprotein E, and is less reactive with arterial proteoglycans compared with LNG treatment. The inclusion of EE in the triphasic oral contraceptive treatment was sufficient to negate the potentially atherogenic effects of LNG on LDL composition.

Animals↗
PubMed1996

Effects of hormone replacement modalities on low density lipoprotein composition and distribution in ovariectomized cynomolgus monkeys.

This study was designed to determine the effect of several hormone replacement therapies on LDL size, density, heterogeneity, and composition in surgically postmenopausal cynomolgus monkeys fed an atherogenic diet. Groups (n = 5 each) of ovariectomized cynomolgus monkeys were untreated (control), or treated with conjugated equine estrogens, medroxyprogesterone acetate (progesterone), combined estrogen-progesterone, or tamoxifen for 9 weeks. There were no differences among treatment groups in total plasma, LDL, or HDL cholesterol or triglyceride concentrations. Plasma LDL were isolated by ultracentrifugation and size exclusion chromatography and subfractionated by density gradient centrifugation for subsequent chemical analysis. Estrogen treatment was associated with significantly smaller (measured as LDL molecular weight, 3.9 +/- 0.2 g/mu mol) and denser plasma LDL (1.034 g/ml peak density) compared with control (4.5 +/- 0.1 g/mu mol; 1.030 g/ml peak density) or progesterone-treated animals (4.6 +/- 0.2; 1.029 g/ml peak density). LDL from the estrogen group were relatively enriched in protein and triglyceride and poor in cholesteryl ester and apolipoprotein F (apoE) compared to the control group. Triglyceride enrichment with estrogen treatment occurred predominantly in the lighter, larger LDL subfractions (d = 1.015-1.025 g/ml), which were reduced in concentration (26 +/- 10 mg cholesterol/dl) compared to control (61 +/- 19 mg/dl) or progesterone treated animals (67 +/- 16 mg/dl). Combined estrogen-progesterone or tamoxifen treatment resulted in changes in LDL that followed the same trend as those observed with estrogen treatment. We conclude that short-term estrogen treatment of ovariectomized cynomolgus monkeys results in changes in plasma LDL size, density, and composition while having no apparent effect on overall plasma lipid concentrations.

Administration, Oral↗