Search PubMed⌕ Search

Biomedical subjects

K Wolf

Publications and source records attributed to K Wolf.

At least 91 records · Page 5Linked to original sources
PubMed1997

Lack of control by immediate early response genes in the oxygen regulation of erythropoietin gene expression.

This study sought to investigate the role of immediate early genes in the stimulation of erythropoietin (EPO) gene expression by hypoxia. To this end freshly isolated rat hepatocytes were exposed to either normoxia (20% oxygen) or to hypoxia (1% oxygen) and the mRNA levels of the early genes c-fos, c-jun, c-myc and EGR-1 were monitored together with EPO mRNA. Isolation of the cells from the livers strongly stimulated the expression of c-fos, c-jun, c-myc and of EGR-1, whilst EPO gene expression remained unchanged. Exposure of the isolated hepatocytes to hypoxia did not further change early gene expression when compared with cells kept under normoxic conditions. EPO mRNA increased time dependently with a delay of 1 h after onset of hypoxia. These findings suggest that even strong activation of early gene expression has no influence on EPO gene expression, whilst activation of EPO gene expression during hypoxia can happen without change of early gene expression. It appears, therefore, as if immediate early genes are not causally involved in the sequence of events by which hypoxia stimulates EPO gene expression.

Animals↗
PubMed1997

ANP gene expression in rat hearts during hypoxia.

It is unclear whether the increase in plasma atrial natriuretic peptide (ANP) concentration during hypoxia is due to direct, hypoxia-induced upregulation of ANP secretion in the heart, or to pressure overload of the right ventricle (RV) following hypoxia-induced pulmonary hypertension. To test the hypothesis that hypoxia leads to an early upregulation of the ANP gene, we examined the influence of acute and prolonged inspiratory hypoxia (6 h, 1 or 3 weeks) on the expression of ANP messenger ribonucleic acid (mRNA) in rat heart and compared the results with the expression of the ANP gene after acute pressure overload induced by experimental coarctation of the main pulmonary artery. As a molecular marker for hypertrophy we determined the ratio of alpha- and beta-myosin gene expression. Hypoxia increased systolic RV pressure from 20.0 +/- 1.6 mmHg to 27.8 +/- 1.6 mmHg (P < 0.01) and 41.6 +/- 2.1 mmHg (P < 0. 05) after 1 and 3 weeks hypoxia respectively. The ANP plasma concentration did not change significantly after 6 h or 1 week: 232 +/- 21 pg/ml (control), 246 +/- 25 pg/ml (6 h), 268 +/- 25 pg/ml (1 week), but increased significantly after 3 weeks hypoxia (446.8 +/- 99.56 pg/ml; P < 0.05). ANP mRNA levels in different regions of the heart did not change after 6 h or 1 week hypoxia. After 3 weeks hypoxia ANP mRNA had increased 2.7-fold in the RV (P < 0.05), 4. 2-fold in the left ventricle (LV, P < 0.05), 3.5-fold in the septum (S, P < 0.05) and about 1.4-fold in the right (n.s.) and left atrium (n.s.). Relative ventricular masses increased significantly only for the RV (190%, P < 0.05) during hypoxia. The beta/alpha-myosin mRNA ratio did not change after 6 h hypoxia but, contrary to ANP gene expression, increased after just 1 week (6.1-fold in RV, 7.8-fold in LV, 6-fold in S; P < 0.05) and was more pronounced in the RV after 3 weeks (9.4-fold in RV, 7.6-fold in LV, 9.1-fold in S; P < 0.05). The increase in the beta/alpha-myosin mRNA ratio in the LV contrasts with a lack of increase in relative ventricular mass. Acute pressure overload in the RV after pulmonary arterial banding significantly increased ANP-mRNA and the beta/alpha-myosin mRNA ratio after 1 day in the RV. In the LV ANP mRNA was unchanged. The delayed upregulation of the ANP gene suggests that hypoxia per se is not a significant stimulus for ANP gene expression in the heart and that hypoxia-induced ANP-gene expression in the heart is regulated predominantly by the increase in RV afterload due to hypoxia-induced increased pulmonary pressure. The upregulation of ANP and beta-myosin mRNA in the LV during chronic hypoxia has yet to be elucidated.

Animals↗
PubMed1997

In vivo carbon monoxide exposure and hypoxic hypoxia stimulate immediate early gene expression.

This study aimed to examine the influence of acute tissue hypoxygenation on the expression of immediate early genes in different rat tissues. To this end male Sprague-Dawley rats were exposed to 0.1% carbon monoxide for 0.5, 1 and 6 h or to 9% oxygen for 6 h and mRNA levels for c-jun, c-fos, c-myc and EGR-1 were assayed by RNase protection in hearts, kidneys, livers and lungs. We found that hypoxia increased c-jun mRNA levels between twofold (lung) and eightfold (liver) in all organs examined; c-fos mRNA increased between three-fold (lung) and 20-fold (heart); c-myc mRNA increased between twofold (lung) and sixfold (heart); and EGR-1 mRNA increased between twofold (lung) and sixfold (heart). Our findings suggest that acute tissue hypoxygenation is a general stimulus of the expression of immediate early genes in vivo. With regard to the sensitivity to hypoxia, organ differences appear to exist in that the lung is rather insensitive, whilst the heart is rather sensitive.

Animals↗
PubMed1997

Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro.

This study examined the expression of EPO, VEGF and VEGF receptor gene under conditions of reduced oxygen supply in primary cultures of rat hepatocytes, and compared it with the expression of these genes in hypoxic rat livers in vivo. To this end we exposed male Sprague-Dawley rats to hypoxia (10% and 8% O2), carbon monoxide (0.1% CO) or injected cobalt chloride (60 mg/kg CoCl2) subcutaneously. For the in vitro experiments we used primary cultures of rat hepatocytes which were kept at high (20% O2) and low (1% O2) oxygen tensions for three hours. The EPO mRNA was up-regulated by hypoxia in vitro and in vivo about 10-fold. The VEGF mRNA was up-regulated fivefold in the hepatocytes only, whereas the in vivo mRNA levels remained unchanged. The mRNA levels of flt-1 were up-regulated threefold by 8% O2 in livers, dependent on the strength of hypoxia (10% caused no changes in flt-1 gene expression) and on the kind of hypoxic stimulus (8% O2 was as effective as 0.1% CO and more effective than cobalt). The mRNA levels of flk-1/KDR and flt-4 remained unchanged in the liver. In vitro there were no changes in the mRNA levels of flt-1, flt-4 and flk-1/KDR. Consequently, the in vivo regulation of VEGF, which might be modulated by induction of flt-1 receptor gene expression, differs from the in vitro cell culture situation and might be different from the EPO regulation in vivo.

Animals↗
PubMed1996

Late pulmonary impairment following allogeneic bone marrow transplantation.

The pulmonary function of 88 consecutive leukemic patients who had undergone allogeneic bone marrow transplantation (BMT) was studied beforehand, at 3 months, at 6 months, and annually thereafter until 5 years after grafting. The parameters for function which are indicative for obstructive and restrictive lung disease deteriorated in all patient groups during the first 3 to 6 months after BMT but partially recovered within one year. Long-term decline in lung function was similar in all patient groups, and neither the onset nor the magnitude of pulmonary dysfunction was related to the occurrence of pulmonary impairment within 6 months after grafting. Multivariate analysis was then employed to assess predictors for long-term pulmonary disease. Despite the obvious effect of chronic graft versus host disease on the course of lung function, it was in itself not a significant predictor of long-term pulmonary outcome. Rather, the conditioning regimen turned out to be indicative; compared with busulfan, fractionated total body irradiation was demonstrated to be clearly superior with a lower incidence of both restrictive and obstructive long-term lung impairment. Our data indicate a previously unknown long-term side effect of busulfan conditioning.

Adult↗
PubMed1996

Divergent regulation of vascular endothelial growth factor and of erythropoietin gene expression in vivo.

There is accumulating evidence from in vitro experiments that the gene expression of the vascular endothelial growth factor (VEGF) is, like that of the erythropoietin (EPO) gene, regulated by the oxygen tension and by divalent cations such as cobalt. Since the information about the regulation of VEGF gene expression in vivo is rather scarce, this study aimed to examine the influence of hypoxia and of cobalt on VEGF gene expression in different rat organs and to compare it with that on EPO gene expression. To this end male Sprague-Dawley rats were exposed to carbon monoxide (0.1% CO), hypoxia (8% O2 ) or to cobalt chloride (12 and 60 mg/kg s.c.) for 6 h. mRNA levels for VEGF- 188, -164, and -120 amino acid isoforms in lungs, hearts, kidneys and livers were semiquantitated by RNase protection. For these organs we found a rank order of VEGF mRNA abundance of lung >> heart > kidney = liver. EPO mRNA levels were semiquantitated in kidneys and livers. Hypoxia, CO and cobalt increased EPO mRNA levels 60-fold, 140-fold and 5-fold, respectively, in the kidneys, and 11-fold, 11-fold and 3-fold, respectively, in the livers. None of these manoeuvres caused significant changes of VEGF mRNA in lung, heart or kidneys. Only in the livers did hypoxia lead to a significant (50%) increase of VEGF mRNA. These findings suggest that, in contrast to the in vitro situation, the expression of the VEGF gene in normal rat tissues is rather insensitive to hypoxia. In consequence, the in vivo regulation of the VEGF and the EPO genes appear to differ substantially, suggesting that the regulation of the VEGF and EPO genes may not follow the same essential mechanisms in vivo.

Animals↗
PubMed1996

Microalbuminuria screening by reagent strip predicts cardiovascular risk in hypertension.

OBJECTIVE: We tested the hypothesis that qualitative microalbuminuria (MAU) screening in a practice setting would identify non-diabetic hypertensive patients at high risk of developing cardiovascular disease. DESIGN: We enrolled general practitioners throughout Germany, who obtained histories, physical examinations, and routine laboratory values as clinically indicated on treated or non-treated hypertensive, non-diabetic patients. MAU was measured with a albumin-sensitive, immunoassay test strip. We studied 11 343 non-diabetic hypertensive patients. RESULTS: The patients' mean age was 57 years, 51% were men and mean hypertension duration was 69 months. Twenty-five per cent had coronary artery disease, 17% had left ventricular hypertrophy, 5% had had a stroke, and 6% had peripheral vascular disease. MAU was present in 32% of men and 28% of women (P < 0.05). In patients with MAU, 31% had coronary artery disease, 24% had left ventricular hypertrophy, 6% had had a stroke, and 7% had peripheral vascular disease. In patients without MAU, these rates were 22%, 14%, 4%, and 5% respectively: lower in every category (P < 0.001). Further, in patients with coronary artery disease, left ventricular hypertrophy, stroke, and peripheral vascular disease, MAU was significantly greater than in patients who did not have these complications (P < 0.001). MAU increased with age, severity of hypertension and duration of hypertension, was associated with higher plasma creatinine values, and was more common in patients with hyperlipidemia (P < 0.05). CONCLUSION: On the basis of our survey, we conclude that qualitative MAU determinations identify hypertensive patients with particular cardiovascular risk in a practice setting.

Aged↗
PubMed1996

Angiotensin II receptor gene expression in hypertrophied left ventricles of rat hearts.

OBJECTIVE: To examine the expression of angiotensin II AT1a, AT1b and AT2 receptor genes in the left ventricles of rats subjected to ventricular pressure overloading induced by aortic banding for 6 weeks and then 6 weeks medical treatment. RESULTS: Aortic banding was related to an increase in relative weight of the left ventricle from 1.73 +/- 0.06 (sham-operated) to 2.81 +/- 0.25 g/kg, an increase in beta-myosin: alpha-myosin messenger RNA (mRNA) ratio from 0.30 +/- 0.02 to 1.94 +/- 0.55 and an 18-fold increase in left ventricular atrial natriuretic peptide mRNA levels. In contrast, left ventricular pressure overload hypertrophy was not related to a significant change in the abundance of AT1a and AT1b mRNA, which were expressed in a relative ratio of 5:1. Similarly, the abundance of AT2 mRNA was not significantly changed in hypertrophied ventricles. In rats receiving the angiotensin II AT, receptor antagonist losartan (40 mg/kg) for 6 weeks after banding, relative heart weights were 2.39 +/- 0.14 g/kg, the beta-myosin: alpha-myosin ratio was 1.04 +/- 0.20 and atrial natriuretic peptide mRNA levels displayed a blunted increase (11-fold over sham-treated controls), documenting a significant amelioration of left ventricular hypertrophy by blockade of the AT1 receptor. CONCLUSION: Losartan treatment in parallel did not affect AT1a, AT1b and AT2 receptor mRNA levels, which were not different from those in vehicle-treated or sham-treated controls. These findings confirm that left ventricular hypertrophy in the rat is associated with increased ventricular expression of beta-myosin and of atrial natriuretic peptide and with reduced expression of alpha-myosin. Despite these significant changes in cardiac gene expression no alteration was observed in AT1a, AT1b and AT2 receptor mRNA levels.

Angiotensin II↗
PubMed1996

Cobalt but not hypoxia stimulates PDGF gene expression in rats.

This study was done to investigate the influence of different forms of acute tissue hypoxia on the expression of platelet-derived growth factor (PDGF) A chain (PDGF-A) and PDGF B chain (PDGF-B) genes in different rat organs. We found that acute normobaric hypoxia (8% O2), carbon monoxide inhalation (0.1% CO), or lowering the hematocrit to 12% for 6 h had no effect on PDGF-A or PDGF-B gene expression in lung, heart, kidney, and liver of Sprague-Dawley rats. Subcutaneous administration of cobaltous chloride dose dependently increased PDGF-B mRNA by 125% in lungs, by 60% in kidneys, but not in heart and liver. These findings suggest that acute tissue hypoxygenation is not a significant stimulus for PDGF-A and PDGF-B gene expression in these major rat organs. Cobalt appears to cause a tissue-specific increase of PDGF-B gene expression.

Administration, Cutaneous↗
PubMed1996

Messenger ribonucleic acid levels of collagenase (MMP-13) and matrilysin (MMP-7) in virgin, pregnant, and postpartum uterus and cervix of rat.

Evidence indicates that matrix metalloproteinases (MMPs) are essentially involved in the postpartum involution of the uterus. As little information exists about the gene regulation of those MMPs in the uterus, this study aimed to characterize the time course of messenger RNA (mRNA) levels of rat collagenase (MMP-13) and matrilysin (MMP-7) in virgin, late pregnant (18th and 21st day), and postpartum rats (1, 2, 3, and 4 days postpartum). Rat collagenase (MMP-13) mRNA levels were very low in virgin and pregnant animals, but increased transiently 30-fold postpartum, reaching a maximum on the second day postpartum. The temporal course of mRNA levels of matrilysin (MMP-7) shows similarity with that of collagenase mRNA levels, but at any stage the abundance of matrilysin mRNA was at least 100-fold higher than that of collagenase. In virgin animals, matrilysin mRNA levels were dependent on the estrous cycle, being 3- to 4-fold higher in the estrous and diestrous stages than during metestrus. MMP-7 shows an approximately 25-fold induction when comparing the mRNA levels in late pregnancy and 2 days postpartum. In cervexes of virgin, pregnant, and postpartum groups, collagenase mRNA was not detectable. Matrilysin in cervix shows temporal mRNA expression similar to that in uterus, with a maximum on day 1 postpartum. In cervix, we found a 14-fold induction when comparing levels in late pregnancy and those 1 day postpartum. Taken together, our findings suggest that the increased activity of MMPs in the postpartum uterus is due to a strong increase in the mRNA levels of MMP-13 and MMP-7.

Animals↗
PubMed1996

Effect of antihypertensive treatment on qualitative estimates of microalbuminuria.

We tested the utility of qualitative microalbuminuria (MAU) screening in an office practice setting, in assessing the response of MAU to drug treatment. We enrolled general practitioners throughout Germany, who obtained histories, physical examinations, and routine laboratory values as clinically indicated on > 6000 non-treated hypertensive, nondiabetic patients. MAU was measured with an albumin-sensitive, immunoassay test strip. The patients were then assigned to monotherapy by their physicians with carvedilol, angiotensin-converting enzyme (ACE) inhibitors, beta blockers, calcium channel blockers, diuretics, and other single regimens in an open-label fashion. The goal was diastolic pressure < 90 mm Hg or at least a 10 mm Hg decrease in systolic (S) and diastolic blood pressure (DBP). The patients' mean age was 57 years and 51% were men. The mean known hypertension duration was 69 months. MAU was present in 37% of men and 34% of women. All regimens lowered BP. All regimens caused large numbers of MAU patients to revert by 3 months. MAU reversal occurred in patients less than 65 years as well as in those 65 years or older. Multiple regression analysis indicated that systolic and DBP reduction, duration of hypertension, and body size were most associated with MAU reversal. Thus, MAU determinations reverted to negative with antihypertensive treatment in many patients. BP reduction was the single most important variable in reversing MAU. All drug regimens were effective. We conclude that qualitative MAU detection is useful not only for screening, but also for follow-up nondiabetic patients with hypertension in an office practice setting.

Aged↗