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H Drexler

Publications and source records attributed to H Drexler.

At least 55 records · Page 3Linked to original sources
PubMed2001

Role of G beta-subunit in angiotensin II-type 1 receptor signaling.

The G-protein-coupled angiotensin II-type 1 (AT1) receptor activates the mitogen-activated protein (MAP) kinase cascade and the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) cascade via tyrosine phosphorylation. Recent observations indicated that the G beta-subunit of heterotrimeric G-proteins interacts with tyrosine phosphorylated proteins. We investigated whether angiotensin II (ANG II) activates MAP-kinases and JAK/STAT cascades via the G beta-subunit. In rat aortic smooth muscle (RASM) cells we found phosphorylated proteins associated with the G beta-subunit SHC (Sequence Homology of Collagen) and JAK2. We demonstrate that JAK2 activity increased upon G beta-binding. The activity of pp60(c-src) kinase also increased, but upon activation pp60(c-src) dissociates from the G beta-complex. Immunoprecipitations revealed that SHC forms a complex with JAK2. Blockade of JAK2 with AG490 abolished this complex formation; therefore, JAK2 may be the kinase responsible for SHC phosphorylation. Thus, the G beta-subunit may play a pivotal role in AT1-receptor signaling by connecting signaling cascades leading to cell growth and differentiation.

Angiotensin II↗
PubMed2001

The role of interleukin-6 in the failing heart.

Clinical studies have shown that circulating levels of interleukin (IL)-6 and other IL-6 related cytokines are increased in patients with congestive heart failure (CHF). Plasma IL-6 concentrations are related to decreasing functional status of the patient and provide important prognostic information. Experimental studies have produced compelling evidence that IL-6 and IL-6 related cytokines play a pivotal role in the regulation of cardiac myocyte hypertrophy and apoptosis. This review summarizes clinical and experimental data from this rapidly evolving field, which, taken together, strongly suggest that IL-6 and IL-6 related cytokines are intricately involved in the pathophysiology of the failing heart.

Animals↗
PubMed2000

Role of NAD(P)H oxidase in angiotensin II-induced JAK/STAT signaling and cytokine induction.

Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O(2)(-)) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O(2)(-) anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT(1)) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O(2)(-) anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O(2)(-) anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II-induced phosphorylation of JAK2, STAT1alpha/ss, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47(phox), a NAD(P)H oxidase subunit, abolished Ang II-induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 micromol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O(2)(-) anions generated by the NAD(P)H oxidase system, and O(2)(-) anion-dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II-induced IL-6 synthesis. Thus, Ang II-induced inflammatory effects seem to require O(2)(-) anions generated by the NAD(P)H oxidase system.

Angiotensin II↗
PubMed2000

Cardioprotective effects of the Na(+)/H(+) exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA.

BACKGROUND: Activation of Na(+)/H(+) exchange in myocardial ischemia and/or reperfusion leads to calcium overload and myocardial injury. Experimental studies have shown that Na(+)/H(+) exchange inhibitors can attenuate Ca(2+) influx into cardiomyocytes. We therefore performed a multicenter, randomized, placebo-controlled clinical trial to test the hypothesis that inhibition of Na(+)/H(+) exchange limits infarct size and improves myocardial function in patients with acute anterior myocardial infarction (MI) treated with direct PTCA. METHODS AND RESULTS: One hundred patients were randomized to receive placebo (n=51) or a 40-mg intravenous bolus of the Na(+)/H(+) exchange inhibitor cariporide (HOE 642) (n=49) before reperfusion. Global and regional left ventricular functions were analyzed by use of paired contrast left ventriculograms performed before and 21 days after PTCA and myocardial enzymes (ie, creatine kinase ¿CK, CK-MB, and LDH) as markers for myocardial tissue injury were evaluated. At follow-up, the ejection fraction was higher (50% versus 40%; P<0.05) and the end-systolic volume was lower (69.0 versus 97.0 mL; P<0.05) in the cariporide group. Significant improvements in some indices of regional wall motion abnormalities were observed, such as the percentage of chords with hypokinesis < -2 SD (P=0.045) and the severity of hypokinesis in the border zone of the infarct region (P=0.052). In addition, CK, CK-MB, or LDH release was significantly reduced in the cariporide patients. CONCLUSIONS: Our findings suggest that inhibition of Na(+)/H(+) exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.

Adult↗
PubMed2000

Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation.

BACKGROUND: Increased inactivation of nitric oxide by oxygen free radicals contributes to endothelial dysfunction in patients with coronary artery disease (CAD). We therefore determined the activity of extracellular superoxide dismutase (EC-SOD), the major antioxidant enzyme system of the vessel wall, and its relation to flow-dependent, endothelium-mediated dilation (FDD) in patients with CAD. METHODS AND RESULTS: SOD isoenzyme activity was determined in coronary arteries from 10 patients with CAD and 10 control subjects. In addition, endothelium-bound EC-SOD activity (eEC-SOD), released by heparin bolus injection, and FDD of the radial artery were measured in 35 patients with CAD and 15 control subjects. FDD, determined by high-resolution ultrasound, was assessed at baseline, after intra-arterial infusion of vitamin C, N-monomethyl-L-arginine, and combination of both. EC-SOD activity in coronary arteries (control subjects: 126+/-14; CAD: 63+/-11 U/mg protein; P<0.01) and eEC-SOD activity in vivo (control subjects: 14.5+/-1.1; CAD: 3.8+/-1.1 U. mL(-1). min(-1); P<0.01) were reduced in patients with CAD. Activity of eEC-SOD was positively correlated with FDD (r=0.47; P<0. 01) and negatively with the effect of the antioxidant vitamin C on FDD (r=-0.59; P<0.01). In young individuals with hypercholesterolemia, however, eEC-SOD activity was increased (21. 0+/-1.2 U. mL(-1). min(-1); n=10; P<0.05). CONCLUSIONS: In patients with CAD, vascular EC-SOD activity is substantially reduced. The close relation between endothelium-bound EC-SOD activity and FDD suggests that reduced EC-SOD activity contributes to endothelial dysfunction in patients with CAD. In young hypercholesterolemic individuals, however, endothelium-bound EC-SOD activity is increased and may, in part, counteract impairment of endothelial function as the result of increased formation of oxygen free radicals.

Adult↗
PubMed2000

Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability.

BACKGROUND: Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. METHODS AND RESULTS: Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT(1)) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT(1) receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. CONCLUSIONS: Ang II, AT(1) receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT(1) receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.

Angina, Unstable↗
PubMed2000

The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system : relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes.

BACKGROUND: Fas (APO-1/CD95) is a transmembrane receptor belonging to the tumor necrosis factor receptor superfamily. Cross-linking of Fas by Fas ligand (FasL), a tumor necrosis factor-alpha-related cytokine, promotes apoptosis and/or transcription factor activation in a highly cell-type-specific manner. The biological consequences of Fas activation in cardiomyocytes and the regulation of Fas and FasL abundance in the myocardium in vivo remain largely unknown. METHODS AND RESULTS: As shown by immunohistochemistry, Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. Moreover, FasL was constitutively expressed in the myocardium and in isolated cardiomyocytes, as revealed by reverse transcription polymerase chain reaction and Western blotting. Left ventricular abundance of Fas but not FasL was upregulated in a rat model of compensated volume-overload hypertrophy and was closely related to diastolic but not systolic wall stress as determined by MRI. Cardiomyocyte apoptosis was not enhanced in volume-overload hypertrophy despite the increased expression of Fas and the presence of FasL in the myocardium. Moreover, injection of mice with an agonistic anti-Fas antibody promoted hepatocyte but not cardiomyocyte apoptosis in vivo. Stimulation of isolated cardiomyocytes with recombinant FasL promoted an activation of the transcription factor AP-1 as shown by electrophoretic mobility shift assays but did not induce cell death. CONCLUSIONS: Fas and FasL are constitutively expressed in the myocardium and in cardiomyocytes. Myocardial expression of Fas is closely related to diastolic loading conditions in vivo. Signaling pathways emanating from Fas are coupled to an activation of the transcription factor AP-1 in cardiomyocytes.

Animals↗
PubMed2000

Percutaneous penetration studies for risk assessment.

During the last few years the general interest in the percutaneous absorption of chemicals has increased. It is generally accepted that there is very few reliable quantitative and qualitative data on dermal exposure to chemicals in the general population and in occupationally exposed workers. In order to predict the systemic risk of dermally absorbed chemicals and to enable agencies to set safety standards, data is needed on the rates of percutaneous penetration of important chemicals. Standardization of in vitro tests and comparison of their results with the in vivo data could produce internationally accepted penetration rates and/or absorption percentages very useful for regulatory toxicology. The work of the Percutaneous Penetration Subgroup of EC Dermal Exposure Network has been focussed on the standardization and validation of in vitro experiments, necessary to obtain internationally accepted penetration rates for regulatory purposes. The members of the Subgroup analyzed the guidelines on percutaneous penetration in vitro studies presented by various organizations and suggested a standardization of in vitro models for percutaneous penetration taking into account their individual experiences, literature data and guidelines already in existence. During the meetings of Percutaneous Penetration Subgroup they presented a number of short papers of up to date information on the key issues. The objective was to focus the existing knowledge and the gaps in the knowledge in the field of percutaneous penetration. This paper is an outcome of the meetings of the Percutaneous Penetration Subgroup and reports the presentations on the key issues identified throughout the 3-year duration of the Dermal Exposure Network (1997-1999).

Journal Article↗
PubMed2000

Exposure assessment and sensitisation in workers exposed to organic acid anhydrides.

OBJECTIVES: To clarify whether the intensity of exposure to organic acid anhydrides (OAAs) is associated with the risk of sensitisation to these allergens. METHODS: The investigations were carried out in three different manufacturing plants (A, B, and C) where OAAs were used in the production of epoxy resins. Methyltetrahydrophthalic acid anhydride (MTHPA) was used in all three plants. The exposure assessment included stationary and ambient air monitoring (OAAs in the air) and biological monitoring (metabolites in urine). In plant A 20, in plant B 86 and in plant C 113 employees were examined by a physician (anamnesis, skin-prick test, specific IgE, spirometry). In plants B and C, the exposure areas were classified as high, medium, and low, without the results of the exposure assessment being known. RESULTS: The ambient air concentrations (in microg/m3) of MTHPA were 37.2 and 58.5 in plant A (number of samples n = 2), ranged from <0.5-26.2 in plant B (n = 5) and from 2.1-57.9 in plant C (n = 3) with stationary air collecting, and from 8-45 (n = 6), from < 4.7-35.7 (n = 3) and from 2-37.8 (n = 3) with personal air collection. The metabolites of OAAs in urine (in nmol/mmol creatinine) ranged from 5.7-645 (median of MTHPA: 346) in plant A, from < 1-213 (median of MTHPA: 10.1) in plant B and from 0.1-830 (median of the sum of the OOA metabolites: 108.6) in plant C. The prevalence of sensitisation was 35% in plant A, 21% in plant B and 29% in plant C. A higher prevalence in the highly exposed areas, however, could not be seen. Levels of IgE specific for conjugates of MTHPA were not associated with the metabolites in the end of shift urine. Levels of IgG specific for conjugates of MTHPA, however, were associated with the metabolites in the end of shift urine. CONCLUSIONS: The data showed that biological monitoring is a useful tool in the exposure assessment of OAAs. Comparing the prevalence of sensitisation and the results of biological monitoring, between the three plants, we found that sensitisation increased with increasing exposure. Within a plant a higher risk of sensitisation in persons working in highly exposed areas at the time of the examination could not be seen, possibly due to frequent job rotation.

Adult↗
PubMed2000

Protein kinase G reverses all isoproterenol induced changes of cardiac single L-type calcium channel gating.

OBJECTIVE: cGMP reduces the effect of beta-adrenoceptor agonists on cardiac L-type calcium current by protein kinase G activation. Stimulation of beta-adrenoceptors increases protein kinase A dependent phosphorylation of L-type calcium channels via cAMP. At the single channel level, protein kinase A dependent phosphorylation increases both availability and open probability. The present study investigates how cGMP antagonises protein kinase A induced changes of single L-type calcium channel gating. METHODS: Single L-type calcium channels were recorded in the cell attached configuration of the patch clamp technique in isolated mouse ventricular myocytes. RESULTS: The beta-adrenoceptor agonist isoproterenol (10(-6) M) enhanced single channel peak average current by increasing availability and open probability and decreasing the time constant of long close times. 8-Br-cGMP (10(-3) M) completely reversed these effects. The phosphatase inhibitor okadaic acid (10(-6) M) did not influence the effect of 8-Br-cGMP. The protein kinase G inhibitor Rp-8Br-PET-cGMPS (10(-7) M) abated the effect of 8-Br-cGMP. Activation of protein kinase A by the hydrolysis-resistant cAMP derivative 8-Br-cAMP (10(-3) M) enhanced L-type calcium channel activity like isoproterenol and its effect was also reversed by 8-Br-cGMP. CONCLUSION: 8-Br cGMP diminishes beta-adrenoceptor activation of L-type calcium channels via protein kinase G. It interacts with the beta-adrenoceptor signaling pathway distal of adenylyl cyclase. Our observations suggest that protein kinase G interacts either with protein kinase A or directly with the L-type calcium channel.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Endothelial dysfunction in hypercholesterolemia: mechanisms, pathophysiological importance, and therapeutic interventions.

Since the demonstration of the obligatory role of the endothelium in arterial relaxation by Furchgott and Zawadzki (1980), there has been great interest in the role of the endothelium in vascular disease. Apart from endothelium-dependent vasodilation, other important functions of the endothelium have now been studied, that is, the regulation of adhesion and infiltration of leukocytes and inhibition of platelet adhesion and aggregation. Many functions of the endothelium are influenced by nitric oxide (NO), which is synthesized by endothelial NO synthase. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Multiple factors contribute to this, including increased inactivation of NO by radicals and inhibition of NO formation by different mechanisms. The functional implications of endothelial dysfunction are not completely defined. However, recent studies suggest that endothelial dysfunction contributes to myocardial perfusion abnormalities. Furthermore, endothelial dysfunction may play an important role with respect to development and progression of atherosclerosis because the endothelium is involved in the regulation of key events of the atherosclerotic process. Endothelial dysfunction in hypercholesterolemia is reversible by cholesterol-lowering treatment, that is treatment with HMG-CoA-reductase inhibitors. First experimental data suggest that maneuvers that increase the bioavailability of NO in hypercholesterolemia may even result in regression of preexisting atherosclerotic lesions.

Animals↗
PubMed2000

Myocardial "hybrid" revascularisation with minimally invasive direct coronary artery bypass grafting combined with coronary angioplasty: preliminary results of a multicentre study.

OBJECTIVE: To expand the benefits of the minimally invasive direct coronary artery bypass (MIDCAB) concept to patients with multivessel disease, a hybrid procedure combining surgical revascularisation of the left anterior descending artery with interventional procedures for additional coronary lesions has recently been introduced. Preliminary results in patients undergoing this hybrid procedure are presented. DESIGN AND PATIENTS: Since December 1996, 35 patients (29 male, 6 female, mean (SD) age 56.7 (17) years) underwent a hybrid revascularisation performed as a primary MIDCAB procedure for grafting of the left anterior descending artery with the left internal mammary artery, followed by staged angioplasty and stenting of additional coronary lesions. RESULTS: After MIDCAB grafting the postoperative course was uneventful in all patients. Coronary reangiography after a median of seven days revealed patent and functioning left internal mammary artery grafts in all patients. Applying subsequent percutaneous transluminal coronary angioplasty and occasional stenting (n = 14), a total of 47 lesions were treated successfully. Procedure related complications did not occur. All patients remained free from angina and no stress ECG changes were recorded. CONCLUSIONS: The preliminary results of this hybrid approach to myocardial revascularisation suggest that this is a safe and effective procedure for complete revascularisation in selected patients with multivessel disease. Elderly and reoperative patients with significant comorbidity may benefit especially from such hybrid procedures by avoiding cardiopulmonary bypass and mid sternotomy.

Adult↗