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Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase
Abstract
Platelets play a key role in hemostasis through their ability to rapidly adhere to activated or injured endothelium, subendothelial matrix proteins, and other activated platelets. A strong equilibrium between activating and inhibiting processes is essential for normal platelet and vascular function, impairment of this equilibrium being associated with either thrombophilic or bleeding disorders. Both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) have been established as crucial and synergistic intracellular messengers that mediate the effects of platelet inhibitors such as nitric oxide (NO) and prostacyclin (PG-I2). However, it was recently suggested that a rapid cGMP/cGMP-dependent protein kinase (cGK)–mediated extracellular signal-related kinase (ERK) phosphorylation promotes platelet activation. This hypothesis was examined here by evaluating established and proposed cGK activators/inhibitors with respect to their capacity to promote either platelet activation or inhibition. In particular, the regulatory role of cGK for ERK phosphorylation and thrombin-, thromboxane-, and VWF-induced platelet activation was investigated. The data obtained do not support the concept that cGK-mediated ERK phosphorylation promotes platelet activation but confirm the inhibitory role of cGK in platelet function. One explanation for these discrepancies is the novel finding that extracellular cGMP analogs potently and rapidly inhibit thrombin-, thromboxane-, and VWF-induced human platelet signaling and activation by a cGK-independent mechanism.
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“NO is a potent inhibitor of PLT aggregation, acting via activation of soluble guanylyl cyclase in PLTs (64, 65).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [64]
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“NO is a potent inhibitor of PLT aggregation, acting via activation of soluble guanylyl cyclase in PLTs (64, 65).”
InfluentialFunction of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion
Hofmann, F. B., Feil, R., Kleppisch, T., & Schlossmann, J. (2005) · Physiological Reviews · doi:10.1152/physrev.00015.2005 · Cited by 402
“Platelet activation by cGKI might involve increased secretion of the platelet agonist ADP (160, 223), but the in vivo relevance of cGKI-stimulated platelet aggregation remains to be shown (82, 175).”
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Self-citationMechanisms of flavonoid protection against myocardial ischemia–reperfusion injury
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“The anti-platelet effect of flavonoids may be due to increased production of prostacyclin [36] which via synthesis of cAMP reduce platelet aggregation [178].”
BackgroundNO/cGMP-Dependent Modulation of Synaptic Transmission
Feil, R., & Kleppisch, T. (2007) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-74805-2_16 · Cited by 192
“However, it is emerging that the presently available “cGK inhibitors” might be less specific than previously thought and, therefore, produce effects not related to cGK inhibition (Burkhardt et al. 2000; Gambaryan et al. 2004; Marshall et al. 2004; Feil R et al. 2005a).”
BackgroundSignalling through the platelet glycoprotein Ib-V–IX complex
Canobbio, I., Balduini, C., & Torti, M. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.05.008 · Cited by 151
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Self-citationIRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation
Antl, M., von Brühl, M.-L., Eiglsperger, C., Werner, M. E., Konrad, I., Köcher, T., Wilm, M. S., Hofmann, F. B., Maßberg, S., & Schlossmann, J. (2006) · Blood · doi:10.1182/blood-2005-10-026294 · Cited by 145
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ResultAburima, A. A., Wraith, K. S., Raslan, Z., Law, R., Magwenzi, S., & Naseem, K. M. (2013) · Blood · doi:10.1182/blood-2013-03-487850 · Cited by 119
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Self-citationBirschmann, I., & Walter, U. (2004) · Acta Biochimica Polonica · doi:10.18388/abp.2004_3579 · Cited by 115
“Our group (Gambaryan et al., 2004) demonstrated a potent cGK-unrelated inhibition of human platelet activation by both cGK activators and inhibitors, using the conditions published by Li et al. (2003a, 2003b cGKI affects diverse signaling pathways leading to platelet activation.”
MethodSelf-citationEffects of the NO/soluble guanylate cyclase/cGMP system on the functions of human platelets
Makhoul, S., Walter, E., Pagel, O., Walter, U., Sickmann, A., Gambaryan, S. P., Smolenski, A., Zahedi, R. P., & Jurk, K. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.03.008 · Cited by 102
Self-citationRap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets
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cGMP and cGMP-Dependent Protein Kinase in Platelets and Blood Cells
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“This review will focus primarily on platelet inhibition by the intracellular second messengers cAMP and cGMP which play crucial roles in platelet inhibition (Fig. 1) ( Gambaryan et al. 2004; Lohmann and Walter 2005; Munzel et al. 2003; Walter and Gambaryan 2004).”
BackgroundSelf-citationFunction of cGMP-dependent Protein Kinases in the Nervous System
Feil, R., Hofmann, F. B., & Kleppisch, T. (2005) · Reviews in the Neurosciences · doi:10.1515/revneuro.2005.16.1.23 · Cited by 85
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cGMP-binding Prepares PKG for Substrate Binding by Disclosing the C-terminal Domain
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Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide
Jensen, B. O., Selheim, F., Døskeland, S. O., Gear, A. R. L., & Holmsen, H. (2004) · Blood · doi:10.1182/blood-2004-03-1058 · Cited by 71
Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation
Zhang, G., Xiang, B., Dong, A., Skoda, R. C., Daugherty, A., Smyth, S. S., Du, X., & Li, Z. (2011) · Blood · doi:10.1182/blood-2011-03-341107 · Cited by 69
cGMP-dependent protein kinases in drug discovery
Schlossmann, J., & Hofmann, F. B. (2005) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03406-9 · Cited by 69
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“2014), VWF/R (Naseem and Riba 2008; Gambaryan et al. 2004; Marshall et al. 2004; Li et al. 2003) can moderately and NO-independently increase sGC activation and thus cGMP concentration.”
BackgroundInfluentialSelf-citationcGMP Signaling and Vascular Smooth Muscle Cell Plasticity
Lehners, M., Dobrowinski, H., Feil, S. C., & Feil, R. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5020020 · Cited by 72
“For instance, “cGKI-specific” cGMP analogues may have effects independent of cGKI [54,55].”
BackgroundInhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro
Pierre, S., Crosbie, L., & Duttaroy, A. K. (2005) · Platelets · doi:10.1080/09537100500129540 · Cited by 64
“cGMP is known to inhibit platelet aggregation [20].”
BackgroundThe NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
Danielewski, O., Schultess, J., & Smolenski, A. (2005) · Thrombosis and Haemostasis · doi:10.1160/th04-09-0582 · Cited by 62
“However, these data were challenged by others (40, 41).”
BackgroundTracking functions of cGMP-dependent protein kinases (cGK)
Suzanne, M. L. (2005) · Frontiers in bioscience · doi:10.2741/1621 · Cited by 62
Reduced Vascular NO Bioavailability in Diabetes Increases Platelet Activation In Vivo
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The Role of NO/sGC/cGMP/PKG Signaling Pathway in Regulation of Platelet Function
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Platelet regulation by NO/cGMP signaling and NAD(P)H oxidase-generated ROS
Begonja, A. J., Teichmann, L. L., Geiger, J., Gambaryan, S. P., & Walter, U. (2006) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2005.12.028 · Cited by 56
“phosphorylation, clearly ruled out a stimulatory role of cGK I in platelet function [16,17].”
BackgroundSelf-citationUnresolved roles of platelet nitric oxide synthase
Naseem, K. M., & RIBA, R. (2008) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2007.02802.x · Cited by 54
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“For western blot analysis, WP were added directly to sodium dodecyl sulfate (SDS) gel-loading buffer and analyzed by SDSpolyacrylamide gel electrophoresis (PAGE), as described.(57) The separated proteins were transferred to a nitrocellulose membrane and incubated with the primary antibody overnight at 4 1C.”
MethodSelf-citationRukoyatkina, N., Walter, U., Friebe, A., & Gambaryan, S. P. (2011) · Thrombosis and Haemostasis · doi:10.1160/th11-05-0319 · Cited by 49
“For Western blot analysis WP were added directly to sodium dodecyl sulphate (SDS) gel loading buffer, then analysed by SDS polyacrylamide gel electrophoresis (PAGE) as described (37).”
MethodSelf-citationPhosphorylation of CalDAG‐GEFI by protein kinase A prevents Rap1b activation
Subramanian, H., Zahedi, R. P., Sickmann, A., Walter, U., & Gambaryan, S. P. (2013) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12271 · Cited by 49
Self-citationBladowski, M., Gawryś, J., Gajecki, D., Szahidewicz-Krupska, E., Sawicz-Bladowska, A., & Doroszko, A. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2979260 · Cited by 46
“Some of the authors suggested that contamination platelet samples by leukocytes account for suspected platelet NO production [114].”
BackgroundMethodA heretical view on the role of NO and cGMP in vascular proliferative diseases
Feil, R., Feil, S. C., & Hofmann, F. B. (2005) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.12.001 · Cited by 45
Викторович, М. И., Gambaryan, S. P., Kehrer, L., Schuetz, C., Kobsar, A. L., Rukoyatkina, N., Nikolaev, V. O., Кривченко, А. И., Watson, S. P., Walter, U., et al. (2011) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2011.817 · Cited by 44
“Human platelet rich plasma (PRP) was prepared as described previously (13) with minor modifi cations.”
MethodSelf-citationValtcheva, N., Nestorov, P., Beck, A., Russwurm, M., Hillenbrand, M., Weinmeister, P., & Feil, R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806161200 · Cited by 43
RIBA, R., Oberprieler, N. G., Roberts, W., & Naseem, K. M. (2006) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2006.02195.x · Cited by 42
Phosphoproteomics of human platelets: A quest for novel activation pathways
Zahedi, R. P., Begonja, A. J., Gambaryan, S. P., & Sickmann, A. (2006) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2006.08.017 · Cited by 41
Self-citationSun, Z., Lü, F., Cheng, J., Zhang, M., Zhang, Y., Xiong, W., Zhao, Y., & Qu, H. (2018) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2018.1492419 · Cited by 41
“Among which, PLTs are essential for primary haemostasis and repair of the endothelium [40,41].”
BackgroundYang, H., Jin, S., Jang, H., Kim, J., Lee, J., Kim, J., & Kim, H.-S. (2019) · Scientific Reports · doi:10.1038/s41598-019-44190-7 · Cited by 40
Aburima, A. A., Walladbegi, K., Wake, J. D., & Naseem, K. M. (2017) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13738 · Cited by 39
The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood
Reiss, C., Викторович, М. И., Bischoff, V., Subramanian, H., Kehrer, L., Friebe, A., Stasch, J., Gambaryan, S. P., & Walter, U. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13286 · Cited by 35
“However, we previously reported (Gambaryan et al., 2004) that PKA and PKG inhibitors show nonspecific effects on platelet function.”
BackgroundSelf-citationRoles of cGMP/cGMP-dependent protein kinase in platelet activation
Walter, U., & Gambaryan, S. P. (2004) · Blood · doi:10.1182/blood-2004-06-2389 · Cited by 33
Self-citationZHANG, S. H., Zhang, Y., Shen, J., Zhang, S., Chen, L., Gu, J., Mruk, J. S., Cheng, G., Zhu, L., Kunapuli, S. P., et al. (2013) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12362 · Cited by 29
Rukoyatkina, N., Butt, E., Subramanian, H., Nikolaev, V. O., Викторович, М. И., Walter, U., Gambaryan, S. P., & Benz, P. M. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.290 · Cited by 29
“Human platelets were prepared and used as previously reported.(43,65) Blood was obtained from healthy volunteers according to our institutional guidelines and the Declaration of Helsinki.”
MethodSelf-citationPediaditakis, P., Js, K., He, L., Zhang, X., Graves, L. M., & Lemasters, J. J. (2010) · Biochemical Journal · doi:10.1042/bj20091741 · Cited by 28
Rukoyatkina, N., Begonja, A. J., Geiger, J., Eigenthaler, M., Walter, U., & Gambaryan, S. P. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07506.x · Cited by 27
“For Western blot analysis WP were added directly to sodium dodecyl sulphate (SDS) gel loading buffer, then analysed by SDS polyacrylamide gel electrophoresis (PAGE) as described (Gambaryan et al, 2004).”
MethodSelf-citationLauver, A. A., Driscoll, E. M., & Lucchesi, B. R. (2008) · Pharmacology · doi:10.1159/000132085 · Cited by 27
Gambaryan, S. P., Subramanian, H., Kehrer, L., Викторович, М. И., Sudnitsyna, J. S., Reiß, C., Rukoyatkina, N., Friebe, A., Sharina, I. G., Martin, E., et al. (2016) · Cell Communication and Signaling · doi:10.1186/s12964-016-0139-9 · Cited by 25
“Human platelets were prepared as reported previously [26].”
MethodSelf-citationDimerization of Nitric Oxide-sensitive Guanylyl Cyclase Requires the α1 N Terminus
Wagner, C., Russwurm, M., Jäger, R., Friebe, A., & Koesling, D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412099200 · Cited by 25
Knowles, R., & Warner, T. D. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.004 · Cited by 26
Викторович, М. И., Fock, E. M., Dobrylko, I. A., Sudnitsyna, J. S., Gambaryan, S. P., & Panteleev, M. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810667 · Cited by 24
“To evaluate whether the differences in platelet reactivity at 37 ◦C and 25 ◦C were related to the activation of PKA/PKG, we analyzed the VASP phosphorylation, which is often used as a marker of these kinase activations [60,61], in platelets under these conditions (Supplementary Figure S6).”
MethodSelf-citationFuentes, F., Alarcón, M. A., Badimón, L., Fuentes, M., Klotz, K., Vilahur, G., Kachler, S., Padró, T., Palomo, I. F., & Eduardo Fuentes, Q. (2017) · International Journal of Cardiology · doi:10.1016/j.ijcard.2017.08.006 · Cited by 23
Bilodeau, M. L., & Hamm, H. E. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.121830 · Cited by 23
“These conclusions have been questioned by two independent groups using similar methods (Gambaryan et al., 2004; Marshall et al., 2004).”
MethodPlatelet nitric oxide signalling in heart failure: role of oxidative stress
Shah, A. M., Passacquale, G., Gkaliagkousi, Ε., Ritter, J. M., & Ferro, A. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr115 · Cited by 19
Burnley-Hall, N., Abdul, F. B., Androshchuk, V., Morris, K., Ossei‐Gerning, N., Anderson, R. A., Rees, A., & James, P. E. (2018) · Thrombosis and Haemostasis · doi:10.1160/th17-06-0394 · Cited by 19
“Both cGMP and cyclic adenosine monophosphate are established synergistic mediators of platelet inhibition, 43 and it has previously been established that combined NO and clopidogrel have a synergistic effect on platelet activation.11 Platelet aggregation plays a key role in the development of…”
BackgroundMultifaceted effects of arachidonic acid and interaction with cyclic nucleotides in human platelets
Rukoyatkina, N., Shpakova, V., Panteleev, M., Kharazova, A., Gambaryan, S. P., & Geiger, J. (2018) · Thrombosis Research · doi:10.1016/j.thromres.2018.09.047 · Cited by 19
Self-citationSchweigel, H., Geiger, J., Beck, F., Buhs, S., Gerull, H., Walter, U., Sickmann, A., & Nollau, P. (2013) · PROTEOMICS · doi:10.1002/pmic.201200353 · Cited by 18
“Reversal of platelet activation by elevated cyclic nucleotide concentration has been reported earlier [41, 42].”
BackgroundSelf-citationGlobular adiponectin increases cGMP formation in blood platelets independently of nitric oxide
RIBA, R., Patel, B., Aburima, A. A., & Naseem, K. M. (2008) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2008.03179.x · Cited by 18
Rauchfuss, S., Geiger, J., Walter, U., Renné, T., & Gambaryan, S. P. (2008) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2008.02925.x · Cited by 18
Self-citationLewis, G. D., Witzke, C. F., Colón-Hernández, P., Guerrero, J. L., Bloch, K. D., & Semigran, M. J. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.11.060 · Cited by 18
“However, several agents that stimulate platelet aggregation, including thrombin, collagen, epinephrine, and adenosine monophosphate, also have been shown to increase platelet cGMP (reviewed in 9). Furthermore, different cGMP analogs appear to either promote (10,11 )o r inhibit platelet aggregation (12, 13 ).”
BackgroundResultInfluentialThe oligopeptide DT‐2 is a specific PKG I inhibitor only in vitro, not in living cells
Gambaryan, S. P., Butt, E., Kobsar, A. L., Geiger, J., Rukoyatkina, N., Parnova, R. G., Nikolaev, V. O., & Walter, U. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02044.x · Cited by 16
“, 2000), we later recognized that they also display PKG-independent unspecific effects on platelets (Gambaryan et al., 2004).”
BackgroundMethodInfluentialSelf-citationCurcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis
Rukoyatkina, N., Shpakova, V., Sudnitsyna, J. S., Panteleev, M., Makhoul, S., Gambaryan, S. P., & Jurk, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105405 · Cited by 14
“Human platelets were prepared as described previously [61,62].”
MethodSelf-citationNavdaev, A., Subramanian, H., Petunin, A., Clemetson, K. J., Gambaryan, S. P., & Walter, U. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093569 · Cited by 13
“We can clearly confirm previous findings [22,23,24,25,36] that vWF/R triggers the sGC/cGMP/PKG pathway (Fig.”
BackgroundResultSelf-citationCyclic nucleotides inhibit MAP kinase activity in low-dose collagen-stimulated platelets
Jackson, E. C. G., & McNicol, A. (2009) · Thrombosis Research · doi:10.1016/j.thromres.2009.06.004 · Cited by 13
“However, other studies have questioned this pathway [23,33,34].”
Koessler, J., Kehrer, L., Gambaryan, S. P., Walter, U., & Kobsar, A. L. (2012) · Thrombosis and Haemostasis · doi:10.1160/th11-07-0461 · Cited by 13
“Previously, NO independent sGC activation in platelets was described in several studies (24, 30, 31), and glycoprotein (GP)Ibα as von Willebrand factor (vWF) receptor was suggested to play an essential role in the mechanism of NO independent sGC activation by vWF (24, 31, 32).”
Self-citationRegulation of the renin-angiotensin-aldosterone system by cyclic nucleotides and phosphodiesterases
Gambaryan, S. P., Mohagaonkar, S., & Nikolaev, V. O. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1239492 · Cited by 12
“For example, much lower concentrations of cGMP analogs are already active in JG cells and platelets (30, 98) than in ZG cells (99).”
BackgroundSelf-citationKim, J., Yang, H., Lee, J., Kim, B.-K., Jin, S., Lee, J., Park, K. W., Cho, H., Kwon, Y., Lee, H., et al. (2016) · Scientific Reports · doi:10.1038/srep36979 · Cited by 11
Brinkley, L. M., Brock, M. A., Stinson, G. P., Bilgili, A., Jacobs, J. P., Bleiweis, M. S., & Peek, G. J. (2024) · Perfusion · doi:10.1177/02676591241228169 · Cited by 9
“47,48 Additionally, NO interacts with cGMP-independent pathways, inhibiting agonist-induced increases in cytosolic Ca2 + concentration and further impeding platelet activation.”
Herfindal, L., Krakstad, C., Myhren, L. E., Hagland, H. R., Kopperud, R. K., Teigen, K., Schwede, F., Kleppe, R., & Døskeland, S. O. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094926 · Cited by 9
“Off-target effects of cyclic nucleotides have been reported in other systems, such as inhibition of platelets [6,7,52].”
BackgroundLavõgina, D., Nickl, C. K., Enkvist, E., Raidaru, G., Lust, M., Vaasa, A., Uri, A., & Dostmann, W. R. (2010) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2010.04.007 · Cited by 8
“The physiological functions of PKGIα involve relaxation of vascular smooth muscle tone [3–5] and prevention of platelet aggregation [6,7].”
BackgroundWen, L., Feil, S. C., & Feil, R. (2017) · Cardiac and vascular biology · doi:10.1007/978-3-319-66224-4_15 · Cited by 8
A modular systems biological modelling framework studies cyclic nucleotide signaling in platelets
Breitenbach, T., Englert, N., Osmanoğlu, Ö., Rukoyatkina, N., Wangorsch, G., Heinze, K. G., Friebe, A., Butt, E., Feil, R., Dittrich, M. T., et al. (2022) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2022.111222 · Cited by 7
Self-citationPark, J. Y., Oh, W. J., Kim, M., Kim, T., Cho, J. Y., Park, H.-J., Lee, I., Kim, S., Kim, G.-S., Kim, S., et al. (2012) · Platelets · doi:10.3109/09537104.2011.629309 · Cited by 7
“Finally, mobilized cGMP inhibits platelet activation through the activation of PKA, generating cAMP [26, 34, 35].”
BackgroundCharacterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol
Knorr, M., Hausding, M., Schulz, E., Oelze, M. W., Rümmler, R., Schuff, A., Daub, S., Schreiner, J., Kröller‐Schön, S., Wenzel, P., et al. (2012) · Pharmacology · doi:10.1159/000339861 · Cited by 7
On the roles of cGMP and glycoprotein Ib in platelet activation
Du, X., Marjanovic, J., & Li, Z. (2004) · Blood · doi:10.1182/blood-2004-02-0507 · Cited by 7
Yaylak, B., Altıntaş, B., Özcan, K. S., Akdeniz, E., Avcı, İ. İ., Zeren, G., Şimşek, B., & Karabay, C. Y. (2018) · Advances in Interventional Cardiology · doi:10.5114/aic.2018.79868 · Cited by 6
“Also, NO is a potent inhibitor of platelet aggregation, acting via activation of soluble guanylyl cyclase in platelets [26, 27].”
BackgroundNygaard, G., Herfindal, L., Kopperud, R., Aragay, A. M., Holmsen, H., Døskeland, S. O., Kleppe, R., & Selheim, F. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.05.032 · Cited by 6
Liu, Y., Zhao, Z., Huang, X., Xiao, Y., Li, N., Yang, W., Feng, R., Feng, W., Long, T., Wu, H., et al. (2025) · Journal of Thrombosis and Haemostasis · doi:10.1016/j.jtha.2025.02.027 · Cited by 4
Potential and limitations of PKA/ PKG inhibitors for platelet studies
Shpakova, V., Rukoyatkina, N., Walter, U., & Gambaryan, S. P. (2021) · Platelets · doi:10.1080/09537104.2021.2003316 · Cited by 4
“H89 and Rp-cGMPS significantly inhibited VASP phosphorylation [8,11], however, both compounds had effects on platelets unrelated to PKA/PKG.”
BackgroundMethodInfluentialSelf-citationNO/cGMP and ROS Pathways in Regulation of Platelet Function and Megakaryocyte Maturation
Begonja, A. J. (2007) · Online Publication Service of Würzburg University (Würzburg University) · Cited by 4
Self-citationCyclic Nucleotide Specificity and Cross-Activation of Cyclic Nucleotide Receptors
Shabb, J. B. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00190-x · Cited by 3
Dervaux, T., Porro, C., Kunzelmann, C., Freyssinet, J., & Martínez, M. C. (2006) · Biochimie · doi:10.1016/j.biochi.2006.04.003 · Cited by 3
NADPH oxidase 2 inhibitor GSK2795039 exerts antiplatelet and antithrombotic activity
Oh, E. B., Kong, Y. J., Kim, T. I., Jang, J., Yu, H., Park, J. W., Kim, S., Kim, T., Sohn, J., & Chang, T.-S. (2025) · Scientific Reports · doi:10.1038/s41598-025-20250-z · Cited by 2
“Consistent with previous reports showing that stirring alone can enhance VASP Ser 239 phosphorylation in human platelets 62 , this condition likely accounts for the elevated baseline levels of VASP phosphorylation observed in our study.”
Fock, E. M., Пронин, Н. А., Rukoyatkina, N., Whaley, A., Gambaryan, S. P., & Whaley, A. O. (2024) · Natural Product Research · doi:10.1080/14786419.2024.2334882 · Cited by 2
Self-citationLighting up kinase action in platelets
Smolenski, A. (2017) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13725 · Cited by 2
Specific PKG inhibitors: do they really exist?
Gambaryan, S. P., Butt, E., Geiger, J., Lohmann, S. M., & Walter, U. (2011) · BMC Pharmacology · doi:10.1186/1471-2210-11-s1-p27 · Cited by 1
“However, several studies have observed no PKG inhibition by KT5823 in intact cells [1] or by Rp-cGMPS analogs in smooth muscle cells [2], as well as unspecific (PKG-independent) effects of Rp-cGMPS analogs in platelets [3].”
BackgroundSelf-citationResponse: yes, cGMP plays a stimulatory role in platelet activation
Li, Z., & Du, X. (2012) · Blood · doi:10.1182/blood-2012-02-410035 · Cited by 1
Peri-operative Decreased cAMP Levels in Long-term Alcoholic Patients
Schoenfeld, H., Franke, R., von Heymann, C., Döpfmer, U., Blaicher, A. M., Ziemer, S., & Spies, C. (2006) · Journal of International Medical Research · doi:10.1177/147323000603400501 · Cited by 1
cGMP and PKG Signaling in Platelets
Gambaryan, S. P., & Walter, U. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00192-3 · Cited by 1
Self-citationRegulation von Plättchenfunktion durch Epac-Proteine
Börgermann, C., Schenck, M., Jakobs, K. H., Schmidt, M., Rubben, H., & Dorp, F. V. (2007) · Der Urologe · doi:10.1007/s00120-007-1427-1
Functional role of cGMP-dependent VASP phosphorylation in vascular cells
Walter, U. (2005) · BMC Pharmacology · doi:10.1186/1471-2210-5-s1-s24
Self-citation
Metadata
- Authors
- Gambaryan, S., Geiger, J., Schwarz, U. R., Butt, E., Begonja, A., Obergfell, A., & Walter, U.
- Affiliations
- University of Würzburg (DE)
- From the Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Germany.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2004-04-01
- Volume
- 103
- Issue
- 7
- Pages
- 2593-2600
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2095417890
- Cited by
- 107
- References
- 27
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 8 · 2017: 5 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 6 · 2012: 5
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- platelet activation, cGMP-dependent protein kinase, ERK1/2 phosphorylation, thrombin, thromboxane, von Willebrand factor, platelet aggregation inhibition, intracellular signaling, hemostasis, thrombosis
- MeSH terms
- Blood Platelets, Calcium, Cyclic GMP, Humans, Kinetics, Platelet Aggregation, Platelet Aggregation Inhibitors, von Willebrand Factor, 8-Bromo Cyclic Adenosine Monophosphate, Cyclic GMP-Dependent Protein Kinases, Nitric Oxide Donors, S-Nitroso-N-Acetylpenicillamine
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