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Biomedical subjects

G Z Feuerstein

Publications and source records attributed to G Z Feuerstein.

At least 19 recordsLinked to original sources
PubMed2005

Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice.

Factor XI (FXI) and factor IX (FIX) are zymogens of plasma serine proteases required for normal hemostasis. The purpose of this work was to evaluate FXI and FIX as potential therapeutic targets by means of a refined ferric chloride (FeCl(3))-induced arterial injury model in factor-deficient mice. Various concentrations of FeCl(3) were used to establish the arterial thrombosis model in C57BL/6 mice. Carotid artery blood flow was completely blocked within 10 min in C57BL/6 mice by application of 3.5% FeCl(3). In contrast, FXI- and FIX-deficient mice were fully protected from occlusion induced by 5% FeCl(3), and were partially protected against the effect of 7.5% FeCl(3). The protective effect was comparable to very high doses of heparin (1000 units kg(-1)) and substantially more effective than aspirin. While FXI and FIX deficiencies were indistinguishable in the carotid artery injury model, there was a marked difference in a tail-bleeding-time assay. FXI-deficient and wild-type mice have similar bleeding times, while FIX deficiency was associated with severely prolonged bleeding times (>5.8-fold increase, P < 0.01). Given the relatively mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable strategy for treating or preventing thrombus formation.

Animals↗
PubMed2004

The Janus face of inflammation in ischemic brain injury.

Brain ischemia elicits an intense inflammatory reaction as evidenced by endogenous activation of microglia and infiltration of leukocytes from the systemic circulation into the brain. A key issue regarding the well-described inflammation in brain injury is whether this reaction is of salutary or detrimental nature in the short and longterm post ischemia. In this brief review, evidence in support for the possible beneficial as well as detrimental role of inflammatory cells and mediators in ischemic brain injury is highlighted. We offer the opinion that both benefits and adverse effects of the inflammatory reaction at large depent on the levels of a specific mediator, the temporal relationships to the injury, the context in which the mediator operates and the spatial relationships to the injury.

Animals↗
PubMed2001

Differential regulation of IL-1beta and TNF-alpha RNA expression by MEK1 inhibitor after focal cerebral ischemia in mice.

Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1beta and TNFalpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n = 8, P < 0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1beta mRNA (59% reduction compared to vehicle, P < 0.01, n = 4) but not TNF-alpha mRNA. A parallel reduction in IL-1beta protein (67%, P < 0.05, n = 6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1beta. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.

Aminoacetonitrile↗
PubMed2001

Receptor binding and biological activity of the dermorphin analog Tyr-D-Arg(2)-Phe-Sar (TAPS).

The binding of Tyr-D-Arg(2)-Phe-sarcosine(Sar)(4) (TAPS), a proposed mu-opioid receptor-selective tetrapeptide analog of dermorphin to opioid receptors, was studied using selective binding assays for subtypes of mu-, delta- and kappa-opioid receptors. Subtype specific mu-opioid receptor binding was further characterized in the presence of sodium and guanosine nucleotides and the activity of TAPS in isolated guinea pig ileum was compared to other mu-opioid receptor-selective ligands. Further, the antinociceptive properties of TAPS following intrathecal (i.t.) administration in rats, as a model of spinal antinociception, were evaluated. The K(i)-values for TAPS at the mu(1)- and mu(2)-opioid receptor sites were 0.4 and 1.3 nM, respectively, suggesting high affinity binding to mu-opioid receptor binding sites with an increased selectivity to mu(1)-opioid receptor sites. The attenuated reduction of TAPS binding at the mu(2)-opioid receptor subtype in the presence of the stable guanosintriphosphate analog 5'-guanylylimidodiphosphate and sodium suggests a potential partial antagonist mode of action at this site.

Analgesics↗
PubMed2001

Apoptosis--new opportunities for novel therapeutics for heart diseases.

Apoptosis as defined by contemporary science describes a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines, (e.g., TNFalpha, FAS) neurohormonal factors (angiotension II), cardiotoxic drugs (e.g., doxorubicin) and mechanical, stretch situations. Several complex signal transduction pathways have been implicated in execution of cardiomyocyte apoptosis. Most prominent are: 1) Tyrosine kinase receptors (TRK) induced signaling involving stress or mitogen activated protein kinases (SAPK/MARK) and sphingolipids metabolites (ceramide); 2) G-protein coupled receptor (GPCR) signaling (Galphai, Galphaq) and 3) NF(K) B activation. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of diverse molecular targets associated with cardiomyocyte apoptosis provide new opportunities for pharmacologic manipulation, that may lead to discovery and development of therapeutic strategies for treatment of heart failure, arrhythmias and myocardial infarction.

Adrenergic beta-Antagonists↗
PubMed2001

Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats.

BACKGROUND AND PURPOSE: CD44 is a transmembrane glycoprotein involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. The present report describes the discovery of upregulated CD44 gene expression and its spatial and temporal distribution in the brain after focal stroke. METHODS: Rats were subjected to permanent occlusion of the middle cerebral artery (MCAO). Suppression subtractive hybridization (SSH) strategy was used to identify differentially expressed genes. Northern blotting and real-time polymerase chain reaction were used to evaluate the expression of CD44 and hyaluronan synthase 2 (HAS-2) mRNA. Western blotting and immunohistochemistry were used to examine CD44 expression and cellular distribution. RESULTS: CD44 upregulation after focal stroke was discovered by the SSH approach and confirmed by DNA sequencing. Northern blot using a pooled poly(A)+ RNA revealed 3 splice variants of CD44 mRNA, and their inducible expression started at 6 hours (5.3-fold increase over sham operation), peaked at 24 hours (28.6-fold increase), and persisted up to 72 hours (17.8-fold increase) after MCAO. A parallel induction profile of HAS-2 mRNA was observed in the ischemic brain tissue. The levels of CD44 were markedly elevated at 6 hours (1.8-fold increase over sham; n=3), 24 hours (2.9-fold, peak induction; P<0.01), and 72 hours (2.4-fold increase; P<0.05) after MCAO by means of Western analysis. Immunohistochemical and confocal microscopy confirmed that constitutive expression of CD44 is limited to microvessels in normal brain but is strongly induced after ischemia, where the immunoreactive signal mainly resided in endothelial cells and monocytes. Double-labeling immunohistochemistry demonstrated that a marked induction of CD44 in the ischemic lesion is dominantly located in microglia and a subset of macrophages. CONCLUSIONS: The discovery of concomitant induction of CD44 and HAS-2 mRNA expression and the localization of CD44 in the microglia, macrophages, and microvessels of the ischemic brain tissue suggest that an active interaction between CD44 and hyaluronan may occur and play a role in the known inflammatory response and tissue remodeling after stroke.

Alternative Splicing↗
PubMed2000

Comparing the antithrombotic efficacy of a humanized anti-factor IX(a) monoclonal antibody (SB 249417) to the low molecular weight heparin enoxaparin in a rat model of arterial thrombosis.

A humanized inhibitory anti-factor IX(a) antibody (SB 249417) has been compared to enoxaparin (Lovenox) in a rat model of arterial thrombosis. Pretreatment of rats with either SB 249417 (3.0 mg/kg, i. v.) or enoxaparin (30.0 mg/kg, i.v. or s.c.) resulted in comparable and significant reductions in thrombus formation. However, the efficacious dose of enoxaparin resulted in >30-fold increase in the aPTT over baseline, while the efficacious dose of SB 249417 prolonged the aPTT by only approximately 3-fold. Additionally, pretreatment with SB 249417 resulted in sustained blood flow and arterial patency throughout the experiment in >80% of rats treated. In contrast, <30% of rats pretreated with enoxaparin remained patent throughout the experiment. The data in this report indicate that the selective inhibition of factor IX(a) with the monoclonal antibody SB 249417 produces a superior antithrombotic profile to that of the low molecular weight heparin enoxaparin.

Animals↗
PubMed2000

Monocyte chemoattractant protein-1 is upregulated in rats with volume-overload congestive heart failure.

BACKGROUND: Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF). METHODS AND RESULTS: An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288+/-22, 502+/-62, and 826+/-138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5, P:<0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of (125)I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3+/-57.0, 181.3+/-8.8, and 123.3+/-14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively). CONCLUSIONS: Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.

Animals↗
PubMed2000

Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty.

Interleukin-1beta (IL-1beta) is a pleiotropic cytokine capable of inducing smooth muscle activation and leukocyte recruitment in restenosis and atherosclerosis. Our present study investigated the expression of IL-1beta, IL-1 receptor antagonist (IL-1ra), and IL-1 receptor (IL-1RI and IL-1RII) mRNA in carotid artery after balloon angioplasty using semiquantitative reverse transcription/polymerase chain reaction (RT/PCR) and Northern analysis. Time course studies revealed that IL-1beta mRNA was rapidly induced at 6 h (30-fold increase over control, P < 0.001) post balloon injury and diminished to basal levels at 24 h. The increased expression of IL-1ra mRNA was delayed, reaching a peak at 24 h (400-fold increase, P < 0.001) and sustained up to 14 days. The expression of IL-1RII mRNA was remarkably similar to that of IL-1beta, whereas the IL-1RI (the signaling receptor) mRNA expression was delayed (significantly induced at day 1; 14.2-fold increase, P < 0.01) post balloon injury. Immunohistochemical studies revealed a strong induction of IL-1beta in the area with actively proliferating and migrating smooth muscle cells (i.e., in the inner medial layer at day 1 and in neointima at day 14 after balloon injury). The differential but concomitant expression of IL-1beta, IL-1ra, IL-1RI, and IL-1RII mRNAs after balloon angioplasty suggests that each of these IL-1 system components may play a distinct role in neointima formation.

Angioplasty, Balloon↗
PubMed2000

Benign focal ischemic preconditioning induces neuronal Hsp70 and prolonged astrogliosis with expression of Hsp27.

We have established a focal preconditioning (PC) paradigm that produces significant and prolonged ischemic tolerance (IT) of the brain to subsequent permanent middle cerebral artery occlusion (MCAO). PC using 10 min of MCAO induces brain tolerance at 1-7 days of reperfusion that requires active protein synthesis. The protective protein(s) involved are unknown. In these studies the increased transcription and translation of the inducible 70-kDa heat shock protein (Hsp70) and the 27-kDa heat shock protein (Hsp27), and astrogliosis/glial fibrillary acidic protein (GFAP) were determined by Northern analysis and immunohistochemistry following PC. Cellular localization of proteins was determined by double labeling. PC produced no brain injury but did increase Hsp70 mRNA transiently at 6 h and increased Hsp27 mRNA later at 24 h for at least 5 days. Protein expression induced by PC exhibited a similar profile. Hsp70 protein was primarily expressed in neurons from 1 to 5 days post-PC throughout the PC cortex. Hsp27 protein expression was initiated later for a much longer period of time. A remarkable astroglyosis was verified with increased astrocytic Hsp27 from 1 to 7 days after PC. Gliosis with increased Hsp27 in the PC cortex was still present but reduced 4 weeks after PC. Therefore, PC that results in brain tolerance/neuroprotection increases neuronal Hsp70 in the PC cortex and activated astrocytic Hsp27 in the PC cortex in a temporal fashion associated with developing IT. The short duration of benign ischemia (PC) that produces IT produces a robust, long-lived cellular and protein synthetic response that extends throughout the entire cortex (i.e. well beyond the MCA perfusion territory). The resulting IT is associated with changes in astrocyte-activation that might provide increased support and protection from injury. Although both Hsp70 and Hsp27 may participate in the neuroprotection/brain tolerance induced by PC, the temporal expression patterns of these proteins indicate that they are not solely responsible for the tolerance to brain injury.

Animals↗
PubMed2000

Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart.

Three major mammalian mitogen-activated protein kinases, extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal protein kinase (JNK), have been identified in the cardiomyocyte, but their respective roles in the heart are not well understood. The present study explored their functions and cross talk in ischemia/reoxygenation (I/R)-induced cardiac apoptosis. Exposing rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 mitogen-activated protein kinases was noted; peak activities increased (fold) by 5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I/R identified 18.6% of the cells as showing morphological features of apoptosis, which was further confirmed by DNA ladder and terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL). Myocytes treated with PD98059, a MAPK/ERK kinase (MEK1/MEK2) inhibitor, displayed a suppression of I/R-induced ERK activation, whereas p38 and JNK activities were increased by 70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 inhibitor, or SB203580, a p38 and JNK2 inhibitor, I/R+PD98059-induced apoptotic cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats treated with PD98059 and subjected to global ischemia (30 minutes)/reoxygenation (1 hour) showed a diminished functional recovery compared with the vehicle group. Coadministration of SB203580 attenuated the detrimental effects of PD98059 and significantly improved cardiac functional recovery. The data taken together suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis in cardiomyocytes subjected to I/R, and the dynamic balance of their activities is critical in determining cardiomyocyte fate subsequent to reperfusional injury.

Animals↗
PubMed2000

Application of real-time polymerase chain reaction to quantitate induced expression of interleukin-1beta mRNA in ischemic brain tolerance.

A short duration of ischemia (i.e., ischemic preconditioning) was shown to result in significant tolerance to subsequent ischemic injury. Since previous reports suggest that interleukin-1beta (IL-1beta) may be involved in both ischemic damage and neuroprotection, the present work examined the expression of IL-1beta mRNA in cortical brain tissue after an established preconditioning (PC) stimulus known to produce significant brain tolerance to focal stroke after 1-7 days. Significant induction of IL-1beta mRNA was observed in the ipsilateral cortex at 6 hr (87+/-9 copies of the mRNA per microgram of brain tissue compared to 16+/-5 copies in sham-operated samples, P < 0.001, n = 4) and 8 hr (46+/-4 copies, P < 0.01, n = 4) after PC by means of real-time Taqman polymerase chain reaction (PCR). The peak expression of IL-1beta mRNA after PC was significantly (P < 0.01) lower than that after permanent occlusion of the middle cerebral artery (MCAO), i.e., 87+/-9 and 546+/-92 copies of RNA per microgram tissue at peak levels for PC and focal stroke, respectively. Immunohistochemistry studies revealed a parallel induction of IL-1beta in the ipsilateral cortex after PC. The maximal expression of IL-1beta was observed during the first week post-PC, showing marked parallelism with the duration of ischemic tolerance. These data suggest that the significant but low levels of IL-1beta induction after PC may contribute to ischemic brain tolerance.

Animals↗
PubMed2000

Antioxidative enzymes in human hearts with idiopathic dilated cardiomyopathy.

The present study investigates intracellular enzymatic pathways involved in the elimination of reactive oxygen species in the left ventricular myocardium of 10 individuals without heart failure and 12 patients with end-stage heart failure due to idiopathic dilated cardiomyopathy. Left ventricular enzyme activities, mRNA and protein levels of the hydrogen peroxide scavenging enzymes catalase (CAT) and glutathione peroxidase (GPX), and the superoxide anion scavenging enzymes mitochondrial (Mn-SOD) and cytosolic (Cu/Zn-SOD) superoxide dismutases were measured. In failing myocardium, there was a significant decrease in CAT activity (4.83+/-0.32 U/mg v 6.59+/-0.52, P<0.01) despite unchanged mRNA expression and protein levels. GPX, Mn-SOD and Cu/Zn-SOD were similar concerning activity, mRNA and protein levels. As indirect free radical markers, similar levels of the products of lipid peroxidation, malondialdehyde and 4-hydroxy-alkenals, and similar tissue nitrotyrosin content were measured. The decrease in CAT activity appears to be a post-transcriptional mechanism. A decreased myocardial capacity to scavenge hydrogen peroxide might lead to a shift in the intracellular redox balance which potentially results in activation of redox sensitive signalling pathways. Direct reactive oxygen species mediated damage was not detected by the methods applied.

Antioxidants↗
PubMed2000

Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways.

Apoptosis is a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and a unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines (FAS/TNF alpha-receptor signaling), stress conditions (chemical or physical, e.g., radiation), sphingolipid metabolites (ceramide) and autocoids, e.g., angiotensin II. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals. This review paper is aimed to highlight the role of protein kinase signaling pathways in apoptosis with special attention to the stress-activated protein kinases (SAPK) and mitogen-activated protein kinases (MAPK) systems.

Adrenergic alpha-Antagonists↗
PubMed2000

Detection of tumor necrosis factor-alpha mRNA induction in ischemic brain tolerance by means of real-time polymerase chain reaction.

A short duration of ischemia (i.e., ischemic preconditioning) results in significant brain protection to subsequent severe ischemic insult. Because previous studies suggest that tumor necrosis factor-alpha (TNF-alpha) plays a role in both promoting ischemic damage and neuroprotection, the present work aimed to evaluate the expression of TNF-alpha mRNA in an established model of ischemic preconditioning using a transient 10-minute occlusion of the middle cerebral artery. Because the level of TNF-alpha mRNA expression in the brain was too low to be consistently detected by Northern technique, a real-time polymerase chain reaction method was applied to quantitate the absolute copy number of TNF-alpha transcript in rat brain after the preconditioning procedure. TNF-alpha mRNA was induced in the ipsilateral cortex as early as 1 hour (27 +/- 1 copies of mRNA per microgram of tissue compared to 11 +/- 3 copies in sham-operated samples) after preconditioning, reached a peak level at 6 hours (49 +/- 10 copies of transcript, n = 4, P < 0.01), and persisted up to 2 days. These data not only demonstrate the utility of real-time polymerase chain reaction for sensitive and accurate measurement of mRNA expression in normal and injured tissues but also suggest a potential role of TNF-alpha in the phenomenon of ischemic preconditioning.

Animals↗