Kroemer, Heyo Klaus

[["dc.bibliographiccitation.firstpage","108"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.lastpage","119"],["dc.bibliographiccitation.volume","144"],["dc.contributor.author","Monzel, Judith V."],["dc.contributor.author","Budde, Thomas"],["dc.contributor.author","Meyer Zu Schwabedissen, Henriette E."],["dc.contributor.author","Schwebe, Matthias"],["dc.contributor.author","Bien-Möller, Sandra"],["dc.contributor.author","Lutjohann, Dieter"],["dc.contributor.author","Kroemer, Heyo K."],["dc.contributor.author","Jedlitschky, Gabriele"],["dc.contributor.author","Grube, Markus"],["dc.date.accessioned","2018-08-17T13:13:19Z"],["dc.date.available","2018-08-17T13:13:19Z"],["dc.date.issued","2017"],["dc.description.abstract","The anthracycline-mediated cardiotoxicity is still not completely understood. To examine the impact of cholesterol metabolism and transport in this context, cholesterol and oxysterol levels as well as the expression of the cholesterol transporters ABCA1 and ABCG1 were analyzed in doxorubicin-treated HL-1 murine cardiomyocytes as well as in mouse model for acute doxorubicin-induced cardiotoxicity. Doxorubicin-treated HL-1 cells exhibited enhanced cholesterol (153+/-20% of control), oxysterol (24S-hydroxycholesterol: 206+/-29% of control) and cholesterol precursor levels (lathosterol: 122+/-12% of control; desmosterol: 188+/-10% of control) indicating enhanced cholesterol synthesis. Moreover, abca1 and abcg1 were upregulated on mRNA, protein and functional level caused by a doxorubicin-mediated activation of the nuclear receptor LXR. In addition, the oxysterols not only induced the abca1 and abcg1 in HL-1 cells but also enhanced the expression of endothelin-1 and transforming growth factor-beta, which have already been identified as important factors in doxorubicin-induced cardiotoxicity. These in vitro findings were verified in a murine model for acute doxorubicin-induced cardiotoxicity, demonstrating elevated cardiac (2.1+/-0.2vs. 3.6+/-1.0ng/mg) and systemic cholesterol levels (105.0+/-8.4vs. 130.0+/-4.3mg/dl), respectively, as well as enhanced oxysterol levels such as cardiac 24S-hydroxycholesterol (2.1+/-0.2vs. 3.6+/-1.0ng/mg). In line with these findings cardiac mRNA expression of abca1 (303% of control) and abcg1 (161% of control) was induced. Taken together, our data demonstrate enhanced cholesterol and oxysterol levels by doxorubicin, resulting in a LXR-dependent upregulation of abca1 and abcg1. In this context, the cytotoxic effects of oxysterols and their impact on cardiac gene expression should be considered as an important factor in doxorubicin-induced cardiotoxicity."],["dc.identifier.doi","10.1016/j.bcp.2017.08.008"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15396"],["dc.language.iso","en"],["dc.notes.status","fcwi"],["dc.relation.eissn","0006-2952"],["dc.title","Doxorubicin enhances oxysterol levels resulting in a LXR-mediated upregulation of cardiac cholesterol transporters"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","105"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Thrombosis and Haemostasis"],["dc.bibliographiccitation.lastpage","115"],["dc.bibliographiccitation.volume","117"],["dc.contributor.author","Schaletzki, Yvonne"],["dc.contributor.author","Kromrey, Marie-Luise"],["dc.contributor.author","Broderdorf, Susanne"],["dc.contributor.author","Hammer, Elke"],["dc.contributor.author","Grube, Markus"],["dc.contributor.author","Hagen, Paul"],["dc.contributor.author","Sucic, Sonja"],["dc.contributor.author","Freissmuth, Michael"],["dc.contributor.author","Völker, Uwe"],["dc.contributor.author","Greinacher, Andreas"],["dc.contributor.author","Rauch, Bernhard H."],["dc.contributor.author","Kroemer, Heyo K."],["dc.contributor.author","Jedlitschky, Gabriele"],["dc.date.accessioned","2018-08-20T12:40:06Z"],["dc.date.available","2018-08-20T12:40:06Z"],["dc.date.issued","2017"],["dc.description.abstract","The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter. We approached this issue by searching for interacting proteins by in vitro binding assays, followed by immunoblotting and mass spectrometry, and by visualising their co-localisation in platelets and haematopoietic cells. We identified the PDZ domain containing scaffold proteins ezrin-binding protein 50 (EBP50/NHERF1), postsynaptic density protein 95 (PSD95), and sorting nexin 27 (SNX27), but also the adaptor protein complex 3 subunit beta3A (AP3B1) and the heat shock protein HSP90 as putative interaction partners of MRP4. The knock-down of SNX27, PSD95, and AP3B1 by siRNA in megakaryoblastic leukaemia cells led to a redistribution of MRP4 from intracellular structures to the plasma membrane. Inhibition of HSP90 led to a diminished expression and retention of MRP4 in the endoplasmic reticulum. These results indicate that MRP4 localisation and function are regulated by multiple protein interactions. Changes in the adaptor proteins can hence lead to altered localisation and function of the transporter."],["dc.identifier.doi","10.1160/TH16-01-0045"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15439"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","0340-6245"],["dc.title","Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1562"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Drug Metabolism and Disposition"],["dc.bibliographiccitation.lastpage","1568"],["dc.bibliographiccitation.volume","44"],["dc.contributor.author","Hubeny, Andrea"],["dc.contributor.author","Keiser, Markus"],["dc.contributor.author","Oswald, Stefan"],["dc.contributor.author","Jedlitschky, Gabriele"],["dc.contributor.author","Kroemer, Heyo K."],["dc.contributor.author","Siegmund, Werner"],["dc.contributor.author","Grube, Markus"],["dc.date.accessioned","2018-08-20T13:06:39Z"],["dc.date.available","2018-08-20T13:06:39Z"],["dc.date.issued","2016"],["dc.description.abstract","Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing Madin-Darby canine kidney (MDCKII) cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50 quinine: 0.7 +/- 1.2 microM; chloroquine: 1.0 +/- 1.5 microM), but no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km 23.4 microM). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs, and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol versus 38 pmol/5 x 10(5) RBCs). Additional transport studies using OCT1-3 and organic cation transporter novel type 1 (OCTN1) indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes."],["dc.identifier.doi","10.1124/dmd.116.069807"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15444"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","0090-9556"],["dc.title","Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","132"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Thrombosis and Haemostasis"],["dc.bibliographiccitation.lastpage","142"],["dc.bibliographiccitation.volume","118"],["dc.contributor.author","Vogt, Katja"],["dc.contributor.author","Mahajan-Thakur, Shailaja"],["dc.contributor.author","Wolf, Robert"],["dc.contributor.author","Bröderdorf, Susanne"],["dc.contributor.author","Vogel, Conny"],["dc.contributor.author","Böhm, Andreas"],["dc.contributor.author","Ritter, Christoph"],["dc.contributor.author","Gräler, Markus"],["dc.contributor.author","Oswald, Stefan"],["dc.contributor.author","Greinacher, Andreas"],["dc.contributor.author","Kroemer, Heyo"],["dc.contributor.author","Jedlitschky, Gabriele"],["dc.contributor.author","Rauch, Bernhard"],["dc.date.accessioned","2020-12-10T18:37:54Z"],["dc.date.available","2020-12-10T18:37:54Z"],["dc.date.issued","2018"],["dc.description.abstract","Sphingosine-1-phosphate (S1P) is a potent lipid mediator released from activated platelets by an adenosine triphosphate (ATP)-dependent export mechanism. A candidate transport protein is the multidrug resistance protein 4 (MRP4/ABCC4), an ATP-dependent transporter highly expressed in platelets. Furthermore, several statins are known to affect platelet functions and exhibit antithrombotic properties. This study determines the involvement of MRP4 in the transport of S1P and a possible interference by statins. Transport studies in membrane vesicles of Sf9 cells containing recombinant human MRP4 revealed that MRP4 mediates ATP-dependent transport of fluorescein- and tritium-labelled S1P. Also, ATP-dependent S1P transport in platelet membrane vesicles containing endogenous MRP4 was inhibited by the MRP inhibitor MK571 and the MRP4-selective compound Ceefourin-1. Confocal microscopy using fluorescein-labelled S1P as well as boron-dipyrromethene (BODIPY)-labelled sphingosine indicated association of S1P and MRP4 in human platelets. In MRP4-deficient mice, agonist-induced S1P secretion was reduced compared with matched wild-type C57Bl/6 mice and platelet S1P concentrations were lower. Fluvastatin and rosuvastatin interfered with MRP4 function inhibiting ATP-dependent cGMP (cyclic guanosine monophosphate) uptake into MRP4-containing vesicles, inhibited MRP4-mediated S1P transport in vitro and significantly attenuated endogenous S1P release from agonist-activated platelet ex vivo. These data suggest that release of S1P from platelets depends on MRP4 and statins can interfere with this transport process. Potentially, this may be relevant for the pleiotropic anti-inflammatory effects of statins and their effect on modulating atherothrombosis."],["dc.identifier.doi","10.1160/TH17-04-0291"],["dc.identifier.eissn","2567-689X"],["dc.identifier.issn","0340-6245"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77133"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","final"],["dc.relation.eissn","0340-6245"],["dc.title","Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","522"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Pharmacogenetics and genomics"],["dc.bibliographiccitation.lastpage","526"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Broderdorf, Susanne"],["dc.contributor.author","Zang, Sebastian"],["dc.contributor.author","Schaletzki, Yvonne"],["dc.contributor.author","Grube, Markus"],["dc.contributor.author","Kroemer, Heyo K."],["dc.contributor.author","Jedlitschky, Gabriele"],["dc.date.accessioned","2018-08-20T13:38:28Z"],["dc.date.available","2018-08-20T13:38:28Z"],["dc.date.issued","2014"],["dc.description.abstract","Multidrug resistance protein 4 (MRP4/ABCC4) has been established as an independent regulator of cyclic AMP (cAMP) levels particularly in vascular smooth muscle cells and in hematopoietic cells. Here, we assessed whether cAMP in turn regulates MRP4. A significant upregulation of MRP4 mRNA and protein by long-term treatment with cAMP-enhancing agents was observed in HeLa cells, smooth muscle cells, and megakaryoblastic leukemia M07e cells. This upregulation was not affected by inhibition of protein kinase A, but could be reverted by inhibitors and siRNA of an alternative cAMP-signaling route involving exchange proteins activated by cyclic AMP (EPAC) and mitogen-activated protein kinases. A selective EPAC activator could equally induce MRP4. The transcriptional regulation was confirmed in a luciferase reporter gene assay using a vector containing a 1494-bp fragment of the promoter region of the MRP4/ABCC4 gene. Our results suggest that enhanced cAMP levels upregulate MRP4 expression, which can result in increased cAMP efflux."],["dc.identifier.doi","10.1097/FPC.0000000000000084"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15447"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1744-6872"],["dc.title","cAMP regulates expression of the cyclic nucleotide transporter MRP4 (ABCC4) through the EPAC pathway"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]