The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Lars Edvinsson - One of the best experts on this subject based on the ideXlab platform.
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Involvement of protein kinases on the Upregulation of endothelin Receptors in rat basilar and mesenteric arteries.
Experimental Biology and Medicine, 2020Co-Authors: Roya Jamali, Lars EdvinssonAbstract:Endothelin B (ET B ) Receptors are upregulated in experimental stroke or after 24 hrs of organ culture. This Upregulation is manifested both as stronger contraction and as an increase in ET B Receptor messenger RNA (mRNA) levels. The present study was designed to evaluate the importance of protein kinases (c-Jun N-terminal kinase [JNK], protein kinase C [PKC], and extracellular signal-regulated kinase [ERK1/2]) in ET B Receptor Upregulation after organ culture. Rat basilar and mesenteric arteries were incubated for 24 hrs in Dulbecco's modified Eagle's medium (DMEM) with or without the PKC inhibitor, RO-31-7549; the ERK1/2 inhibitor, SB386023; or the JNK inhibitor, SP600125, added 3, 6, or 12 hrs after initiation of incubation. Subsequently, vessel segments were mounted in myographs and the contractile responses to ET-1 and sarafotoxin 6c were studied. The ET B and ET A Receptor mRNA levels were determined with a real-time polymerase chain reaction (PCR). The cellular localization and protein level of ET B Receptors were evaluated by immunohistochemistry. The PKC and ERK1/2 inhibitors attenuated the contraction induced by S6c in the basilar arteries more than in the mesenteric arteries. The efficiency of the inhibitors was proportional to the incubation time. Real-time PCR showed a decrease in the ET B Receptor mRNA levels in arteries treated with PKC or ERK inhibitors. The JNK inhibitor had a significant inhibitory effect on ET B Receptor Upregulation in the basilar arteries. Immunohistochemistry revealed that the ET B Receptor Upregulation occured in the smooth-muscle cells and that it had the same pattern as in the quantitative PCR. Our results show that the PKC, ERK1/2, and JNK are more important for the Upregulation of contractile ET B Receptors in cerebral arteries compared with mesenteric arteries. ERK1/2 seems to be more important for the ET B Receptor Upregulation, as compared with PKC and JNK. The evaluation of the time dependency suggests that the phenomenon can be reversed even after its initiation.
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Synergistic effects of a cremophor EL drug delivery system and its U0126 cargo in an ex vivo model.
Drug Delivery, 2019Co-Authors: Simon Topp Christensen, Lars Edvinsson, Sara Ellinor Johansson, Anne-sofie Grell, C. M. Andersson, Kristian Agmund HaanesAbstract:Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ETB) Receptor Upregulation. The current study aimed to determine the optimal dose of U0126 ex vivo and test the toxicology of this dose in vivo. To find the optimal dose and test a suitable in vivo delivery system, we applied an ex vivo model of blood flow cessation and investigated functional ETB Receptor Upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K+ stimuli. Furthermore, an in vivo toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ETB Receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ETB Receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed ex vivo on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ETB Receptor Upregulation. Cremophor EL has an additional positive effect, preventing functional ETB Receptor Upregulation, making it suitable as a drug delivery system.
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The effects of MEK1/2 inhibition on cigarette smoke exposure-induced ET Receptor Upregulation in rat cerebral arteries
Toxicology and Applied Pharmacology, 2016Co-Authors: Na Na Ping, Wei Li, Karin Warfvinge, Lars EdvinssonAbstract:Cigarette smoking, a major stroke risk factor, upregulates endothelin Receptors in cerebral arteries. The present study examined the effects of MEK1/2 pathway inhibition on cigarette smoke exposure-induced ET Receptor Upregulation. Rats were exposed to the secondhand smoke (SHS) for 8 weeks followed by intraperitoneal injection of MEK1/2 inhibitor, U0126 for another 4 weeks. The urine cotinine levels were assessed with high-performance liquid chromatography. Contractile responses of isolated cerebral arteries were recorded by a sensitive wire myograph. The mRNA and protein expression levels of Receptor and MEK/ERK1/2 pathway molecules were examined by real-time PCR and Western blotting, respectively. Cerebral artery Receptor localization was determined with immunohistochemistry. The results showed the urine cotinine levels from SHS exposure group were significantly higher than those from the fresh group. In addition, the MEK1/2 inhibitor, U0126 significantly reduced SHS exposure-increased ETA Receptor mRNA and protein levels as well as contractile responses mediated by ETA Receptors. The immunoreactivity of increased ETA Receptor expression was primarily cytoplasmic in smooth muscle cells. In contrast, ETB Receptor was noted in endothelial cells. However, the SHS-induced decrease in endothelium-dependent relaxation was unchanged after U0126 treatment. Furthermore, SHS increased the phosphorylation of MEK1/2 and ERK1/2 protein in cerebral arteries. By using U0126 could inhibit the phosphorylated ERK1/2 protein but not MEK1/2. Taken together, our data show that treatment with MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA Receptor Upregulation in rat cerebral arteries.
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The Role of ATP and P2X7 in Upregulation of Vasocontractile ET-B Receptors in Basilar Arteries
The FASEB Journal, 2015Co-Authors: Kristian Agmund Haanes, Lars EdvinssonAbstract:Cerebrovascular disease is one of the main causes of death in the developed countries. Several G-protein coupled Receptors, such as the Endothelin-B Receptor (ET-B), are upregulated after a stroke. These Receptors cause constriction in the blood vessels and reduce blood flow, causing further damage and reduced chances of recovery. Our group has previously shown that MEK/ERK1/2 inhibition greatly reduced the Receptor Upregulation and the cerebral damage. Extracellular ATP is a short-range signal important in the regulation of both the blood flow and also in long term cellular modifications. One of the Receptors for ATP, the P2X7 Receptor, is of high interest, as it can be involved in apoptosis, proliferation, and ERK1/2 signaling. We hypothesized that ATP could be an important activator of MEK/ERK1/2 and contribute to the Upregulation of contractile Receptors. Ex vivo ET-B Receptor Upregulation in basilar arteries (assessed by the specific agonist sarafotoxin 6c (S6c) in a myograph) can be induced by incub...
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Early MEK1/2 Inhibition after Global Cerebral Ischemia in Rats Reduces Brain Damage and Improves Outcome by Preventing Delayed Vasoconstrictor Receptor Upregulation
PLOS ONE, 2014Co-Authors: Sara Ellinor Johansson, Gro Klitgaard Povlsen, Stine Schmidt Larsen, Lars EdvinssonAbstract:Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that Upregulation of contractile ETB and 5-HT1B Receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this Receptor Upregulation as a novel target for prevention of cerebral hypoperfusion and delayed neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of Receptor Upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular Receptor Upregulation and thereby improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B Receptors was determined by immunofluorescence. (Less)
Jacob Hansenschwartz - One of the best experts on this subject based on the ideXlab platform.
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erk1 2 inhibition attenuates cerebral blood flow reduction and abolishes etb and 5 ht1b Receptor Upregulation after subarachnoid hemorrhage in rat
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Jacob Hansenschwartz, Petter Vikman, Cangbao Xu, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor Upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
Cangbao Xu - One of the best experts on this subject based on the ideXlab platform.
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MAPK/NF-κB-dependent Upregulation of kinin Receptors mediates airway hyperreactivity: A new perspective for the treatment
Pharmacological Research, 2013Co-Authors: Yaping Zhang, Lars Edvinsson, Lars-olaf Cardell, Cangbao XuAbstract:Airway hyperreactivity (AHR) is a major feature of asthmatic and inflammatory airways. Cigarette smoke exposure, and bacterial and viral infections are well-known environmental risk factors for AHR, but knowledge about the underlying molecular mechanisms on how these risk factors lead to the development of AHR is limited. Activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-kappa B) and their related signal pathways including protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and protein kinase A (PKA) signaling pathways may result in airway kinin Receptor Upregulation, which is suggested to play an important role in the development of AHR. Environmental risk factors trigger the production of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and interleukins (ILs) that activate intracellular MAPK- and NF-kappa B-dependent inflammatory pathways, which subsequently lead to AHR via kinin Receptor Upregulation. Blockage of intracellular MAPK/NF-kappa B signaling prevents kinin B-1 and B-2 Receptor expression in the airways, resulting in a decrease in the response to bradykinin (kinin B-2 Receptor agonist) and des-Arg(9)-bradykinin (kinin B-1 Receptor agonist). This suggests that MAPK- and NF-kappa B-dependent kinin Receptor Upregulation can provide a novel option for treatment of AHR in asthmatic as well as in other inflammatory airway diseases. (C) 2013 Elsevier Ltd. All rights reserved. (Less)
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Cigarette Smoke Upregulates Rat Coronary Artery Endothelin Receptors In Vivo
PLOS ONE, 2012Co-Authors: Yaping Zhang, Lars Edvinsson, Cangbao XuAbstract:Cigarette smoking is a strong cardiovascular risk factor and endothelin (ET) Receptors are related to coronary artery diseases. The present study established an in vivo secondhand smoke (SHS) exposure model and investigated the hypothesis that cigarette smoke induces ET Receptor Upregulation in rat coronary arteries and its possible underlying mechanisms.
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NF-kappaB signaling mediates vascular smooth muscle endothelin type B Receptor expression in resistance arteries.
European journal of pharmacology, 2010Co-Authors: Jian-pu Zheng, Lars Edvinsson, Yaping Zhang, Tord Hjalt, Cangbao XuAbstract:Vascular smooth muscle cells (SMC) endothelin type B (ET(B)) Receptor Upregulation results in strong vasoconstriction and reduction of local blood flow. We hypothesizes that the underlying molecular mechanisms involve transcriptional factor nuclear factor-kappaB (NF-kappaB) pathway. ET(B) Receptor Upregulation and activation of NF-kappaB were studied at functional contraction (in vitro myograph), mRNA (real-time PCR), and protein (Western blot and immunocytochemistry) levels during organ culture of rat mesenteric arteries. Organ culture of the artery segments induced a time-dependent strong contractile response to sarafotoxin 6c in parallel with enhanced expression of ET(B) Receptor mRNA and protein in the SMC. Western blot experiments demonstrated that phosphorylation of NF-kappaB p65 was time-dependently induced during organ culture starting at 1h. In addition, cytoplasmic IkB degradation occurred in parallel with nuclear NF-kappaB accumulation following organ culture. The enhanced expression of ET(B) Receptor protein was apparent at 3h in the SMC and while enhanced ET(B) Receptor-mediated contractions occurred first at 12h. The specific IkappaB inhibitors, IMD-0354 (N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide) and Wedelolactone (7-Methoxy-5,11,12-trihydroxycoumestan), abolished the organ culture induced ET(B) Receptor Upregulation. The intracellular NF-kappaB pathway is involved in the process of induced expression of vascular SMC ET(B) Receptors.
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erk1 2 inhibition attenuates cerebral blood flow reduction and abolishes etb and 5 ht1b Receptor Upregulation after subarachnoid hemorrhage in rat
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Jacob Hansenschwartz, Petter Vikman, Cangbao Xu, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor Upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
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ERK1/2 Inhibition Attenuates Cerebral Blood Flow Reduction and Abolishes ETB and 5-HT1B Receptor Upregulation after Subarachnoid Hemorrhage in Rat:
Journal of Cerebral Blood Flow and Metabolism, 2005Co-Authors: Jacob Hansen-schwartz, Cangbao Xu, Petter Vikman, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor Upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
Petter Vikman - One of the best experts on this subject based on the ideXlab platform.
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Protein kinase C inhibition attenuates vascular ETB Receptor Upregulation and decreases brain damage after cerebral ischemia in rat
BMC Neuroscience, 2007Co-Authors: Marie Henriksson, Emelie Stenman, Petter Vikman, Lars EdvinssonAbstract:Background Protein kinase C (PKC) is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an Upregulation of endothelin Receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin Receptor Upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat.
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erk1 2 inhibition attenuates cerebral blood flow reduction and abolishes etb and 5 ht1b Receptor Upregulation after subarachnoid hemorrhage in rat
Journal of Cerebral Blood Flow and Metabolism, 2006Co-Authors: Jacob Hansenschwartz, Petter Vikman, Cangbao Xu, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor Upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
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ERK1/2 Inhibition Attenuates Cerebral Blood Flow Reduction and Abolishes ETB and 5-HT1B Receptor Upregulation after Subarachnoid Hemorrhage in Rat:
Journal of Cerebral Blood Flow and Metabolism, 2005Co-Authors: Jacob Hansen-schwartz, Cangbao Xu, Petter Vikman, Lars EdvinssonAbstract:Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) Receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase ( MAPK) extracellular signal-regulated kinase ( ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ETB and 5-HT1B Receptor Upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ETA and ETB Receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 Receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ETB and 5-HT1B Receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH. (Less)
Christian Nanoff - One of the best experts on this subject based on the ideXlab platform.
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Hyponatremia and V2 vasopressin Receptor Upregulation: a result of HSP90 inhibition
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian NanoffAbstract:Purpose Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin Receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-Receptors.MethodsExperiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-Receptor and HELA cells with an endogenous V2-Receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-Receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP).ResultsThe results demonstrate a twofold increase in cell-surface Receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-Receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-Receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls.ConclusionSince formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-Receptor Upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.
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Hyponatremia and V2 vasopressin Receptor Upregulation: a result of HSP90 inhibition
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Qiong Yang, Florian Puhm, Michael Freissmuth, Christian NanoffAbstract:Small-molecule inhibitors of heat-shock protein 90 (HSP90) have been under development as chemotherapeutic agents. The adverse events reported from early clinical trials included hyponatremia. Given the limited number of patients enrolled, the number of hyponatremia incidents was remarkable and repeatedly, the event was judged as severe. Inappropriate V2 vasopressin Receptor stimulation is an established cause of hyponatremia. We explored the hypothesis that HSP90 inhibition produces hypersensitivity to vasopressin by upregulating V2-Receptors. Experiments were carried out in cell culture using HEK293 cells with heterologous expression of the human V2-Receptor and HELA cells with an endogenous V2-Receptor complement. We tested the effect of HSP90 inhibition by three structurally unrelated compounds (alvespimycin, luminespib, radicicol) and asserted its specificity in cells depleted of cytosolic HSP90 (by RNA interference). Assays encompassed surface V2-Receptor density and vasopressin-stimulated formation of cyclic AMP (cAMP). The results demonstrate a twofold increase in cell-surface Receptor density following pre-incubation with each of the HSP90 inhibitors. The effect had a concentration-dependence consistent with the individual potencies to inhibit HSP90. Similarly, depletion of cytosolic HSP90 increased surface-Receptor density and at the same time, reduced the inhibitor effect. Upregulated V2-Receptors were fully functional; hence, in culture treated with an HSP90 inhibitor, addition of vasopressin resulted in higher levels of cAMP than in controls. Since formation of cAMP is the first signalling step in raising water permeability of the collecting duct epithelia, we suggest that V2-Receptor Upregulation generates hypersensitivity to vasopressin linking HSP90 inhibition to the development of hyponatremia.