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Biomedical subjects

C Wanner

Publications and source records attributed to C Wanner.

At least 37 records · Page 2Linked to original sources
PubMed2000

CyA and OxLDL cause endothelial dysfunction in isolated arteries through endothelin-mediated stimulation of O(2)(-) formation.

BACKGROUND: Cyclosporin A (CyA) and oxidized low-density lipoprotein (OxLDL) cause endothelial dysfunction, partly through stimulation of O(2)(-) formation (which can inactivate nitric oxide). We investigated whether CyA and OxLDL potentiate their influence on oxidative stress, whether endothelin (ET) is a mediator of CyA- and OxLDL-induced O(2)(-) formation, and whether enhanced oxidative stress results in further attenuation of endothelium-dependent vasodilation. METHODS AND RESULTS: Human LDL was oxidized by Cu(++). O(2)(-) formation of isolated rat aortic rings was measured using a chemiluminescence assay. Incubation (60 min) of aortic rings with CyA (10 ng-10 microg/ml) or with OxLDL (300 microg/ml) caused a significant, dosedependent increase of the basal O(2)(-) formation. Pretreatment of the aortic rings with CyA (10 ng/ml) further enhanced the OxLDL-induced O(2)(-) formation by factor 1.9. The enhancement of the OxLDL-induced stimulation of O(2)(-) formation by CyA could be completely blocked by BQ123, a selective endothelin-1 (ET-1) receptor antagonist. Likewise, exogenously applied ET-1 (1 nM) potentiated the OxLDL-induced O(2)(-) formation by factor 1.8. Endothelium-dependent dilation was measured in isolated rings of rabbit aorta superfused with physiological salt solution in an organ bath. Incubation of the aortic rings with CyA (10 microg/ml, 60 min) or with OxLDL (300 microg/ml, 60 min) alone did not attenuate endothelium-dependent dilations. However, coincubation of the aortic rings with CyA+OxLDL in the presence of diethyl-dithio-carbamate, an inhibitor of the endogenous superoxide dismutase, caused a 60% inhibition of acetylcholine-induced dilator responses. CONCLUSIONS: Coincubation of isolated aortic rings with CyA and OxLDL causes a potent enhancement of vascular O(2)(-) formation. ET-1 seems to be mediator of the CyA-induced O(2)(-) formation. Enhanced oxidative stress results in further attenuation of endothelium dependent vasodilation.

Animals↗
PubMed2000

Impact of dyslipidaemia in renal transplant recipients.

The evidence that lipid disorders in patients following renal transplantation play a major role in the pathogenesis of atherosclerosis and chronic renal allograft rejection is circumstantial. The absolute rate of clinical vascular disease and cardiovascular complications in transplant patients, the high prevalence of an atherogenic lipid profile and the evidence from the large HMG-CoA reductase inhibitor (statin) regression trials in the general population suggest that lipid lowering treatment is necessary in most patients after renal transplantation. Furthermore, animal models and observational studies in patients have found correlations between plasma lipid levels and both acute and chronic rejection. Animal transplant models and clinical trials in heart transplant patients also suggest that statin treatment decrease the incidence of chronic rejection in a manner that may also be independent of lipid lowering. Although the mechanisms behind this protective effect remains unclear, statins may be the first agents to be effective in preventing chronic rejection and in reducing the rate of cardiovascular complication in renal transplant recipients.

Animals↗
PubMed1999

Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity.

The vasomotor and cyclic GMP-elevating activity of YC-1, a novel NO-independent activator of soluble guanylyl cyclase (sGC), was studied in isolated rabbit aortic rings and compared to that of the NO donor compounds sodium nitroprusside (SNP) and NOC 18. Similarly to SNP and NOC 18, YC-1 (0.3-300 microM) caused a concentration-dependent, endothelium-independent relaxation that was greatly reduced by the sGC inhibitor 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ 10 microM; 59% inhibition of dilation induced by 100 microM YC-1) suggesting the activation of sGC as one mechanism of action. Preincubation with YC-1 (3 and 30 microM) significantly increased the maximal dilator responses mediated by endogenous NO in aortic rings that was released upon exposure to acetylcholine, and enhanced the dilator response to the exogenous NO-donors, SNP and NOC 18, by almost two orders of magnitude. Vasoactivity induced by SNP and YC-1 displayed different kinetics as evidenced by a longlasting inhibition by YC-1 (300 microM) on the phenylephrine (PE)-induced contractile response, which was not fully reversible even after extensive washout (150 min) of YC-1, and was accompanied by a long-lasting elevation of intracellular cyclic GMP content. In contrast, SNP (30 microM) had no effect on the vasoconstrictor potency of PE, and increases in intravascular cyclic GMP levels were readily reversed after washout of this NO donor compound. Surprisingly, YC-1 not only activated sGC, but also affected cyclic GMP metabolism, as it inhibited both cyclic GMP break down in aortic extracts and the activity of phosphodiesterase isoforms 1-5 in vitro. In conclusion, YC-1 caused persistent elevation of intravascular cyclic GMP levels in vivo by activating sGC and inhibiting cyclic GMP break down. Thus, YC-1 is a highly effective vasodilator compound with a prolonged duration of action, and mechanisms that are unprecedented for any previously known sGC activator.

Animals↗
PubMed1999

Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.

BACKGROUND: Atherosclerosis, a major problem in patients on chronic hemodialysis, has been characterized as an inflammatory disease. C-reactive protein (CRP), the prototypical acute phase protein in humans, is a predictor of cardiovascular mortality in the general population. We hypothesize that several of the classic, as well as nontraditional, cardiovascular risk factors may respond to acute phase reactions. An activated acute phase response may influence or predict cardiovascular risk. METHODS: In 280 stable hemodialysis patients, serum lipids, apolipoproteins (apo) A-I and B, lipoprotein(a) [Lp(a)], fibrinogen, and serum albumin (Salb) were determined in relation to CRP and serum amyloid A (SAA), two sensitive markers of an acute phase response. Mortality was monitored prospectively over a two year period. RESULTS: Serum CRP and SAA were found to be elevated (more than 8 and more than 10 mg/liter, respectively) in 46% and 47% of the patients in the absence of clinically apparent infection. Patients with elevated CRP or SAA had significantly higher serum levels of Lp(a), higher plasma fibrinogen, and lower serum levels of high-density lipoprotein cholesterol, apo A-I, and Salb than patients with normal CRP or SAA. The rise in Lp(a) concentration was restricted to patients exhibiting high molecular weight apo(a) isoforms. During follow-up, 72 patients (25.7%) had died, mostly due to cardiovascular events (58%). Overall mortality and cardiovascular mortality were significantly higher in patients with elevated CRP (31% vs. 16%, P < 0.0001, and 23% vs. 5%, P < 0.0001, respectively) or SAA (29% vs. 19%, P = 0.004, and 20 vs. 10%, P = 0.008, respectively) and were also higher in patients with Salb of lower than 40 g/liter (44% vs. 14%, P < 0.0001, and 34% vs. 6%, P < 0.0001, respectively). Univariate Cox regression analysis demonstrated that age, diabetes, pre-existing cardiovascular disease, body mass index, CRP, SAA, Salb, fibrinogen, apo A-I, and Lp(a) were significantly associated with the risk of all-cause and cardiovascular mortality. During multivariate regression analysis, SAA, fibrinogen, apo A-I, and Lp(a) lost their predictive values, but age and CRP remained powerful independent predictors of both overall death and cardiovascular death. CONCLUSION: These results suggest that a considerable number of hemodialysis patients exhibit an activated acute phase response, which is closely related to high levels of atherogenic vascular risk factors and cardiovascular death. The mechanisms of activated acute phase reaction in patients on chronic hemodialysis remain to be identified. A successful treatment of the inflammatory condition may improve long-term survival in these patients.

Acute-Phase Reaction↗
PubMed1999

Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: role of oxidative stress.

BACKGROUND: Atherogenic lipoproteins cause injury to the vascular wall in the early phase of atherogenesis. We assessed the effects of native (nLDL) and oxidized (oxLDL) low-density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] on O2- formation and cell death in cultured human umbilical vein endothelial cells (HUVECs) and rabbit aorta (RA). METHODS AND RESULTS: O2- formation of HUVECs and RA segments was not influenced by nLDL, but was dose dependently increased by oxLDL and was moderately increased by nLp(a). oxLp(a) was the most potent stimulus for O2- formation, increasing it in HUVECs by 356% at 5 micrograms/ml and in RA by 294% at 100 micrograms/ml. Apoptosis was detected by DNA fragmentation and Annexin assay in HUVECs and by TUNEL staining in RA. Incubation of HUVECs and RA with oxLDL, but not nLDL, dose and time dependently induced apoptosis with only a minimal effect on necrosis. nLp(a) elicited a small but significant effect on apoptosis, whereas oxLp(a) induced apoptosis more potently than oxLDL in HUVECs and RA and caused necrotic cell death in HUVECs. Induction of apoptosis by oxLDL and oxLp(a) in RA was enhanced by the superoxide dismutase (SOD) inhibitor, diethyl-dithio-carbamate, and was blunted by SOD and catalase in HUVECs and RA, suggesting that O2- formation was involved. The concentration of lysophosphatidylcholine, a lipoprotein oxidation product and stimulus for O2- formation, was significantly enhanced by factor 5 in oxLDL and by factor 7 in oxLp(a) compared with native lipoproteins. CONCLUSION: Atherogenic lipoproteins stimulate O2- formation and induction of apoptosis in HUVECs and RA, and may thereby influence the pathogenesis of atherosclerosis.

Animals↗
PubMed1999

Atherogenic lipoproteins, oxidative stress, and cell death.

BACKGROUND: Glomerulosclerosis and atherosclerosis are chronic inflammatory processes that may be influenced by oxidized lipoproteins, oxidized low-density lipoproteins (oxLDL), and oxidized lipoprotein(a) [oxLp(a)]. We hypothesize that these lipoproteins contribute to the development of glomerulosclerosis and atherosclerosis through the induction of oxidative stress, which influences cell viability. We therefore determined the impact of oxLDL and oxLp(a) on O2- formation and on necrotic and apoptotic cell death in vascular and glomerular cells. METHODS: The impact of human LDL and Lp(a) (oxidized with CuSO4) on O2- formation (detected with a chemiluminescence method), apoptosis, and necrosis (determined with the annexin assay) was studied in cultured human umbilical vein endothelial cells (ECs) and in cultured human mesangial cells (MCs). RESULTS: O2- formation was increased by 10 micrograms/ml oxLDL (by factor 2.5 in ECs) and by 5 micrograms/ml oxLp(a) (by factor 3.5 in ECs). OxLDL and oxLp(a) both significantly and dose-dependently increased the rate of apoptotic cell death in ECs and in MCs, with oxLp(a) being the more potent stimulus that also caused necrosis. The induction of apoptosis by oxLDL and oxLp(a) in ECs and MCs was enhanced by inhibition of the endogenous superoxide dismutase (SOD) with diethyl-dithio-carbamate and was blunted by the antioxidants N-acetylcysteine, vitamin C + E, SOD, and catalase, suggesting that oxidative stress was the stimulus for apoptosis. CONCLUSIONS: These data suggest that oxLDL and oxLp(a) contribute to inflammation by stimulating O2- formation, leading to apoptotic cell death in the vascular wall and in the glomerulus. The oxidized lipoproteins may thereby influence the pathogenesis of atherosclerosis and glomerulosclerosis.

Apoptosis↗
PubMed1999

Simvastatin in nephrotic syndrome. Simvastatin in Nephrotic Syndrome Study Group.

BACKGROUND: Hyperlipidemia of the nephrotic syndrome is a risk factor for the development of systemic atherosclerosis, but it also may aggravate glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA reductase inhibitors are effective in reducing cardiovascular morbidity and mortality. Whether they may influence the progression of glomerular disease is not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of whether or not cholesterol lowering by the HMG-CoA reductase inhibitor simvastatin was superior to placebo treatment in limiting the decline of GFR and reducing proteinuria in nephrotic patients with primary glomerulonephritis. METHODS: This was a prospective, two-year, double-blind trial that included 56 patients with primary glomerulonephritis, hypercholesterolemia due to the nephrotic syndrome (proteinuria > 3 g/24 hr), and a creatinine clearance > 40 ml/min/1.73 m2. They were randomly assigned to treatment with simvastatin or placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels below 120 mg/dl. The objectives were to determine the efficacy and safety of simvastatin, the rate of GFR decline as measured by inulin clearance, and the change in proteinuria over a two-year treatment period. RESULTS: Simvastatin produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides of -39% -47%, +1%, and -30%, respectively. Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related events occurred. Minor events included elevations in serum creatine kinase without clinical symptoms. The course of renal function and of proteinuria during the study are still under evaluation and are not given here. CONCLUSIONS: Long-term treatment with simvastatin in nephrotic patients with hypercholesterolemia is effective and safe.

Adult↗
PubMed1999

Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Die Deutsche Diabetes Dialyse Studie Investigators.

BACKGROUND: Non-insulin-dependent diabetes mellitus dialysis patients have the highest cardiovascular mortality known in any group of patients. Mixed dyslipidemia with moderately elevated low-density lipoprotein (LDL) cholesterol and high levels of triglyceride-rich lipoproteins is common in this condition. It is not known, however, whether patients with type 2 diabetes on dialysis with this form of dyslipidemia derive benefit from lipid-lowering therapy. Recently, drugs have become available that potently lower triglyceride-rich, apoB-containing lipoproteins and thus permit testing of this issue. This is the first trial to address specifically the issue of whether the excessive cardiovascular mortality of patients with type 2 diabetes on dialysis can be lowered by statins. METHODS: The Die Deutsche Diabetes Dialyse Studie is a prospective randomized placebo-controlled trial that tests the hypothesis that atorvastatin, a hydroxymethyl-glutaryl coenzyme A reductase inhibitor, decreases the rate of cardiovascular mortality and of nonfatal myocardial infarction in patients with type 2 diabetes who have been on hemodialysis treatment for no more than two years. The primary endpoint, cardiovascular mortality, includes fatal myocardial infarction, sudden death, death during coronary intervention, death from heart failure, and other coronary causes. Secondary endpoints comprise overall mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular disease, and the mean percentage change in lipid profile from baseline. The trial enrolls 1200 men and women on hemodialysis for less than two years and with type 2 diabetes at 150 centers throughout Germany. Inclusion criteria are age of 18 to 80 years, low-density cholesterol of 80 to 190 mg/dl (2.1 to 4.9 mmol/liter), and triglyceride levels of less than 1000 mg/dl (11.4 mmol/liter). Patients are randomized to cither inactive (placebo) or active (atorvastatin, 20 mg/day) drug therapy. The average duration of follow-up is more than 2.5 years. To protect against a lower than expected rate of events, the trial will be continued until a predetermined fixed number of endpoints occurs in the entire cohort so that the predefined power of the trial will be guaranteed. CONCLUSIONS: This trial was designed to demonstrate that lipid lowering with atorvastatin will improve life expectancy and quality of life in type 2 diabetics on hemodialysis. The resolution of this question is important because the genesis of vascular lesions in this condition is multifactorial and the precise role of dyslipidemia has not been defined.

Adolescent↗
PubMed1999

Immunosuppression enhances atherogenicity of lipid profile after transplantation.

BACKGROUND: Patients after renal transplantation exhibit high cardiovascular morbidity and mortality because of the accumulation of cardiovascular risk factors such as hypertension or dyslipidemia. To elucidate the influence of immunosuppressive therapy on hyperlipidemia, we studied serum lipids and lipoproteins in renal transplant patients who received prednisone and either azathioprine or cyclosporine or triple immunosuppressive therapy. METHODS: Serum lipids and lipoprotein levels were measured in 216 renal transplant patients (81 female and 135 male) with stable graft function of 4.8 +/- 2.3 years (range six months to eight years) after transplantation. Patients were divided into three groups according to one of the following immunosuppressive regimens: (a) prednisone and azathioprine, (b) prednisone and cyclosporine, or (c) prednisone, azathioprine, and cyclosporine. Healthy, age- and sex-matched subjects served as controls. In addition to measurement of total serum lipids, lipoproteins were isolated by preparative ultracentrifugation, and lipids were determined in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) density classes. RESULTS: Total serum triglycerides, VLDL, and LDL triglycerides, as well as VLDL cholesterol were elevated in all renal transplant patients, but elevation was pronounced in female patients. In contrast to total serum cholesterol, which was significantly increased in only female patients, elevation of LDL-triglyceride/apo B ratio was more marked in male patients. Patients in group A exhibited only mild hypertriglyceridemia, whereas triglyceride enrichment in VLDL and LDL was more distinct in group B and was most pronounced in patients of group C. Furthermore, hypertriglyceridemia increased with the dose of administered prednisone. CONCLUSIONS: Immunosuppressive therapy in renal transplant patients leads to accumulation of triglyceride-enriched VLDL and LDL. Triglyceride enrichment in LDL indicates the accumulation of small, dense LDLs, which are known to bear enhanced atherosclerotic risk. This study provides data that underline the use of individually adjusted immunosuppressive therapy and steroid-sparing protocols in renal transplant patients to improve their atherogenic lipoprotein profile.

Apolipoproteins B↗
PubMed1999

Abnormalities in lipoprotein metabolism in hemodialysis patients.

BACKGROUND: Patients on chronic hemodialysis treatment are at elevated atherogenic risk, and dyslipidemia appears to be one of the major risk factors. However, most of these patients exhibit elevated serum triglycerides, whereas serum cholesterol and low-density lipoprotein (LDL) cholesterol levels are in the normal range. This study was therefore designed to examine the influence of hypertriglyceridemia under the condition of hemodialysis and diabetes mellitus on LDL metabolism. METHODS: LDL was isolated from healthy controls, hypertriglyceridemic diabetic patients, and nondiabetic hemodialysis patients (N = 30, 10 in each group), which were separated into six subfractions by density gradient ultracentrifugation and were characterized concerning lipid/protein composition, degree of glycation, and oxidation. Uptake of 125I-labeled LDL was examined via LDL receptors of HepG2 cells and scavenger receptors of mouse peritoneal macrophages. RESULTS: In hemodialysis patients, serum triglycerides were significantly elevated, whereas cholesterol levels were within the normal range. Triglyceride enrichment occurred in the very low-density lipoprotein (VLDL) class and LDL class, and an accumulation of a highly atherogenic small dense LDL subfraction could be detected predominantly in patients with non-insulin-dependent diabetes mellitus. LDL of hemodialysis patients also contained elevated levels of lipid peroxidation products, which were even higher in diabetic patients. Alterations in composition, size, and configuration of LDL from diabetic and nondiabetic patients on hemodialysis impaired LDL receptor-mediated degradation and enhanced the uptake of these modified LDL particles via nonsaturable scavenger receptors. CONCLUSION: Diminished LDL receptor-mediated uptake of modified, triglyceride-rich, small dense LDL most likely leads to accumulation of these lipoproteins in vivo, favoring the development of atherosclerotic lesions. Future clinical studies must demonstrate whether patients will benefit from reducing these atherogenic particles by lipid-lowering intervention.

Apolipoproteins B↗
PubMed1999

Genetic identification of three ABC transporters as essential elements for nitrate respiration in Haloferax volcanii.

More than 40 nitrate respiration-deficient mutants of Haloferax volcanii belonging to three different phenotypic classes were isolated. All 15 mutants of the null phenotype were complemented with a genomic library of the wild type. Wild-type copies of mutated genes were recovered from complemented mutants using two different approaches. The DNA sequences of 13 isolated fragments were determined. Five fragments were found to overlap; therefore nine different genomic regions containing genes essential for nitrate respiration could be identified. Three genomic regions containing genes coding for subunits of ABC transporters were further characterized. In two cases, genes coding for an ATP-binding subunit and a permease subunit were clustered and overlapped by four nucleotides. The third gene for a permease subunit had no additional ABC transporter gene in proximity. One ABC transporter was found to be glucose specific. The mutant reveals that the ABC transporter solely mediates anaerobic glucose transport. Based on sequence similarity, the second ABC transporter is proposed to be molybdate specific, explaining its essential role in nitrate respiration. The third ABC transporter is proposed to be anion specific. Genome sequencing has shown that ABC transporters are widespread in Archaea. Nevertheless, this study represents only the second example of a functional characterization.

ATP-Binding Cassette Transporters↗