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Grenegård, Magnus
Publications (10 of 33) Show all publications
Zegeye, M. M., Matic, L., Lengquist, M., Hayderi, A., Grenegård, M., Hedin, U., . . . Kumawat, A. K. (2023). Interleukin-6 trans-signaling induced laminin switch contributes to reduced trans-endothelial migration of granulocytic cells. Atherosclerosis, 371, 41-53
Open this publication in new window or tab >>Interleukin-6 trans-signaling induced laminin switch contributes to reduced trans-endothelial migration of granulocytic cells
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2023 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 371, p. 41-53Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under pathophysiological conditions is largely unknown. In this study, we aimed to investigate the role of IL-6 in regulating endothelial laminin profile and characterize the impact of altered laminin composition on the phenotype, inflammatory response, and function of endothelial cells (ECs).

METHODS: HUVECs and HAECs were used for in vitro experiments. Trans-well migration experiments were performed using leukocytes isolated from peripheral blood of healthy donors. The BiKE cohort was used to assess expression of laminins in atherosclerotic plaques and healthy vessels. Gene and protein expression was analyzed using Microarray/qPCR and proximity extension assay, ELISA, immunostaining or immunoblotting techniques, respectively.

RESULTS: Stimulation of ECs with IL-6+sIL-6R, but not IL-6 alone, reduces expression of laminin α4 (LAMA4) and increases laminin α5 (LAMA5) expression at the mRNA and protein levels. In addition, IL-6+sIL-6R stimulation of ECs differentially regulates the release of several proteins including CXCL8 and CXCL10, which collectively were predicted to inhibit granulocyte transmigration. Experimentally, we demonstrated that granulocyte migration is inhibited across ECs pre-treated with IL-6+sIL-6R. In addition, granulocyte migration across ECs cultured on LN521 was significantly lower compared to LN421. In human atherosclerotic plaques, expression of endothelial LAMA4 and LAMA5 is significantly lower compared to control vessels. Moreover, LAMA5-to-LAMA4 expression ratio was negatively correlated with granulocytic cell markers (CD177 and myeloperoxidase (MPO)) and positively correlated with T-lymphocyte marker CD3.

CONCLUSIONS: We showed that expression of endothelial laminin alpha chains is regulated by IL-6 trans-signaling and contributes to inhibition of trans-endothelial migration of granulocytic cells. Further, expression of laminin alpha chains is altered in human atherosclerotic plaques and is related to intra-plaque abundance of leukocyte subpopulations.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Atherosclerosis, Chronic inflammation, Diapedesis, Endothelial basement membrane, Plaque stability
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-105279 (URN)10.1016/j.atherosclerosis.2023.03.010 (DOI)000994230600001 ()36996622 (PubMedID)2-s2.0-85150807616 (Scopus ID)
Funder
Knowledge Foundation, 2018-0035Stiftelsen Gamla Tjänarinnor, 2019-00851
Available from: 2023-03-31 Created: 2023-03-31 Last updated: 2023-06-07Bibliographically approved
Wenglén, C., Demirel, I., Göthlin Eremo, A., Grenegård, M. & Paramel Varghese, G. (2023). Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells. European Journal of Pharmacology, 944, Article ID 175570.
Open this publication in new window or tab >>Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells
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2023 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 944, article id 175570Article in journal (Refereed) Published
Abstract [en]

Vascular smooth muscles (VSMCs) are known to be the key drivers of intimal thickening which contribute to early progression of atherosclerosis. VSMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli they could modify the type of matrix proteins produced. Serotonin receptor 2B (5-HT2B receptor/HTR2B) has been implicated in several chronic fibrotic and vascular diseases. Although studies have successfully demonstrated the efficacy of HTR2B blockade in attenuating fibrotic disease, the role of 5-HT2B receptor in TGFβ mediated VSMC differentiation remain largely unknown. In the present study, we investigated the potential of targeting the 5-HT2B receptor to prevent TGFβ induced VSMCs differentiation. Our results showed that 5-HT2B receptors are expressed in human atherosclerotic lesion and HTR2B expression positively correlated to the VSMCs markers. We show that AM1125, a selective 5-HT2B receptor inhibitor, significantly inhibits TGFβ1 induced production of collagen and CTGF. The investigation of underlying mechanisms indicated that 5-HT2B receptor antagonism blocks phospho-Smad2 mediated downstream signaling of TGFβ1 in vascular smooth muscle cells. Collectively, the HTR2B/TGF-β1/Phospho-Smad2 pathway plays a critical role in the regulation of VSMCs differentiation. Our findings might serve 5-HT2B receptor as a therapeutic target to limit TGF-β1 induced VSMC differentiation.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Atherosclerosis, Differentiation, Serotonin receptor, Smad, TGFβ
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-104165 (URN)10.1016/j.ejphar.2023.175570 (DOI)000947341600001 ()36781042 (PubMedID)2-s2.0-85148368908 (Scopus ID)
Funder
Knowledge Foundation, 20190120
Available from: 2023-02-14 Created: 2023-02-14 Last updated: 2023-03-30Bibliographically approved
Grenegård, M., Koufaki, M., Zervou, M., Fotopoulou, T., Lindström, E., Nilsson, K. F., . . . Fransén, K. (2023). The cardioprotective, anti-inflammatory and antithrombotic piperazinyl-purine analogue MK177 is a bifunctional drug with promising therapeutic potential. British Journal of Pharmacology, 180(Suppl. 1), 158-159, Article ID P0855.
Open this publication in new window or tab >>The cardioprotective, anti-inflammatory and antithrombotic piperazinyl-purine analogue MK177 is a bifunctional drug with promising therapeutic potential
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2023 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 180, no Suppl. 1, p. 158-159, article id P0855Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Nitrate ester bearing 6-piperazinyl-purine analogues (denoted MK drugs) are cardioprotective in infarction animal models and act as inhibitors of Janus kinase (JAK) and Rho-associated kinase (ROCK) [1-3]. Despite the presence of nitrate ester moiety, the MK drugs do not release nitric oxide (NO).

Methods: We utilized organic chemistry platforms to design a dinitrate ester derivative denoted MK177, cell-free and cellular assays to elucidate antithrom-botic and anti-ischemic mechanisms. Furthermore, we also used tissue models to analyze vasodilation, and animal models to evaluate drug activities in vivo.

Results: In anesthetized pigs, intravenous infusion of MK177 produced“nitroglycerin-like”effects on vital parameters. Analysis of exhaled air confirmed release of NO. MK177 caused concentration-dependent relaxation of iliac arteries (87±6.8 % relaxation of precontracted arteries, mean value ±SD, n=5) and this effect was mediated by activation of the NO/cyclic GMP signaling pathway. It is noteworthy that other mononitrate or non-nitrate MKs did not cause NO-induced vasodilation. In cellular model systems, MK177 evoked antithrombotic effects by targeting ROCK in a NO-independent manner. Specifically, MK177 inhibited platelet aggregation induced by collagen (72±12.6 % inhibition of aggregation, mean value±SD, n=7). Western blot analyses confirmed that MK177 reduced ROCK-dependent phosphorylation of myosin phosphatase sub-unit (MYPT-1) in platelets. Finally, kinase screening assay revealed that MK177 concentration-dependently inhibited ROCK and JAK (Kd values around 5μM).

Conclusion: We have developed a bifunctional drug molecule, MK177, that acts by NO-dependent and NO-independent mechanisms. MK 177 induced car-diovascular NO effects in vivo and relaxed vessels in vitro. MK177 also prevented blood platelet activation via NO-independent ROCK inhibition. The bifunctional nature of MK177 can be of significance in future management of thrombotic and ischemic disease. Collectively, the novel cardio-protective and bifunctional drug MK177 has promising therapeutic potential.

References:

1. Koufaki M, Fotopoulou T, Iliodromitis EK, Bibli SI, Zoga A, Kremastinos DT, Andreadou I. Discovery of 6-[4-(6-nitroxyhexanoyl)(piperazin-1-yl)]-9H-purine, as pharmacological post-conditioning agent. Bioorg Med Chem. 2012;20(19):5948-5956. https://doi.org/10.1016/j.bmc.2012.07.037

2. Kardeby C, Paramel GV, Pournara D, Fotopoulou T, Sirsjö A, Koufaki M, Fransén K, Grenegård M. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. Eur J Pharmacol. 2019;15(857):172428-172434. https://doi.org/10.1016/j.ejphar.2019.172428

3. Paramel GV, Lindkvist M, Idosa BA, Sebina LS, Kardeby C, Fotopoulou T, Pournara D, Kritsi E, Ifanti E, Zervou M, Koufaki M, Grenegård M, Fransén K. Novel purine analogues regulate IL-1βrelease via inhibition of JAK activity in human aortic smooth muscle cells. Eur J Pharmacol. 2022;15(929):175128-175135. https://doi.org/10.1016/j.ejphar.2022.175128

Place, publisher, year, edition, pages
Macmillan Publishers Ltd., 2023
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-108921 (URN)001043027400113 ()
Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2023-10-13Bibliographically approved
Befekadu, R., Grenegård, M., Larsson, A., Christensen, K. & Ramström, S. (2022). Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction. Biomedicines, 10(2), Article ID 275.
Open this publication in new window or tab >>Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
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2022 (English)In: Biomedicines, E-ISSN 2227-9059, Vol. 10, no 2, article id 275Article in journal (Refereed) Published
Abstract [en]

Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1-3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1-3 days after PCI, but not at 3 months. CRP levels peaked at 1-3 days, while PTX3 was similarly high in both acute and 1-3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1-3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
C-reactive protein, PTX3 protein, ST elevation myocardial infarction, neprilysin, survival analysis, thrombectomy
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-97695 (URN)10.3390/biomedicines10020275 (DOI)000770833500001 ()35203485 (PubMedID)2-s2.0-85123618888 (Scopus ID)
Note

Funding agencies:

Örebro University Hospital Research Foundation

AFA Insurance

Region Örebro County

Available from: 2022-02-28 Created: 2022-02-28 Last updated: 2022-10-31Bibliographically approved
Befekadu, R., Grenegård, M., Larsson, A., Christensen, K. & Ramström, S. (2022). Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction. Scientific Reports, 12(1), Article ID 14762.
Open this publication in new window or tab >>Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 14762Article in journal (Refereed) Published
Abstract [en]

The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI.

Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-101044 (URN)10.1038/s41598-022-18972-5 (DOI)000847803100078 ()36042366 (PubMedID)2-s2.0-85136959494 (Scopus ID)
Funder
Region Örebro County
Note

Funding agencies:

Örebro University Hospital

AFA Insurance

Available from: 2022-09-01 Created: 2022-09-01 Last updated: 2022-10-31Bibliographically approved
Paramel Varghese, G., Lindkvist, M., Idosa, B. A., Sebina, L. S., Kardeby, C., Fotopoulou, T., . . . Fransén, K. (2022). Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells. European Journal of Pharmacology, 929, Article ID 175128.
Open this publication in new window or tab >>Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells
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2022 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 929, article id 175128Article in journal (Refereed) Published
Abstract [en]

Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1β release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1β in AoSMCs, as well as intracellular gene and protein expression of IL-1β and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore. Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Atherosclerosis, IL-1β, Inflammation, JAK inhibitor, NLRP3 inflammasome, Purine analogue
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:oru:diva-100098 (URN)10.1016/j.ejphar.2022.175128 (DOI)35792171 (PubMedID)2-s2.0-85133610041 (Scopus ID)
Funder
Örebro University
Available from: 2022-07-07 Created: 2022-07-07 Last updated: 2022-08-24Bibliographically approved
Lindkvist, M., Zegeye, M. M., Grenegård, M. & Ljungberg, L. (2022). Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells. International Journal of Molecular Sciences, 23(3), Article ID 1448.
Open this publication in new window or tab >>Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 3, article id 1448Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and response. This study evaluated and compared the cellular and molecular responses induced by IL-6 family cytokines in human endothelial cells. A proteomic analysis showed that IL-6 family cytokines induce the release of a range of proteins from endothelial cells, such as C-C motif chemokine ligand 23, hepatocyte growth factor, and IL-6. Pathway analysis indicated that gp130-signaling in endothelial cells regulates several functions related to angiogenesis and immune cell recruitment. The present investigation also disclosed differences and similarities between different IL-6 family cytokines in their ability to induce protein release and regulate gene expression and intracellular signaling, in regards to which oncostatin M showed the most pronounced effect. Further, this study showed that soluble gp130 preferentially blocks trans-signaling-induced responses, but does not affect responses induced by classic signaling. In conclusion, IL-6 family cytokines induce both specific and overlapping molecular responses in endothelial cells, and regulate genes and proteins involved in angiogenesis and immune cell recruitment.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
CCL23, cardiotrophin-1 (CT-1), chemotaxis, ciliary neurotrophic factor (CNTF), hepatocyte growth factor (HGF), interleukin-11 (IL-11), leukemia inhibitory factor (LIF)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-97530 (URN)10.3390/ijms23031448 (DOI)000754525300001 ()35163371 (PubMedID)2-s2.0-85123608892 (Scopus ID)
Available from: 2022-02-15 Created: 2022-02-15 Last updated: 2022-02-21Bibliographically approved
Lunde, N. N., Gregersen, I., Ueland, T., Shetelig, C., Holm, S., Kong, X. Y., . . . Halvorsen, B. (2020). Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages. Atherosclerosis, 296, 74-82
Open this publication in new window or tab >>Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages
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2020 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 296, p. 74-82Article in journal (Refereed) Published
Abstract [en]

Background and aims: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events.

Methods: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry.

Results: In the SUMMIT Malmo cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome.

Conclusions: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Cardiovascular disease, Legumain, Macrophage, Plaque modification, Platelets, Protease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-80851 (URN)10.1016/j.atherosclerosis.2019.12.008 (DOI)000518470200014 ()31870625 (PubMedID)2-s2.0-85076845246 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilSwedish Diabetes Association
Note

Funding Agencies:

University of Oslo  

South-Eastern Norway Regional Health Authority 2018084

Research Council of Norway 144139

Anders Jahres foundation for the Promotion of Science  

UNIFOR  

Blix foundation  Innovative Medicines Initiative (SUMMIT Consortium) IMI-2008/115006

Skåne University Hospital Foundations  

Region Skåne Grants  

Swedish Stroke Foundation 

Nansen foundation 

Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved
Kardeby, C., Paramel Varghese, G., Pournara, D., Fotopoulou, T., Sirsjö, A., Koufaki, M., . . . Grenegård, M. (2019). A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. European Journal of Pharmacology, 857, Article ID 172428.
Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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2019 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed) Published
Abstract [en]

Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Nitric oxide, Platelet inhibitor, Purinergic receptors, Rho associated protein kinase, Thromboxane A2
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-74650 (URN)10.1016/j.ejphar.2019.172428 (DOI)000472711200011 ()31175850 (PubMedID)2-s2.0-85066786586 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Onassis Foundation

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-11-14Bibliographically approved
Fälker, K., Ljungberg, L., Kardeby, C., Lindkvist, M., Sirsjö, A. & Grenegård, M. (2019). Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation. Cellular Signalling, 59, 96-109
Open this publication in new window or tab >>Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation
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2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed) Published
Abstract [en]

The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Cyclic nucleotide, Epinephrine, Human platelets, Nitric oxide, Prostacyclin, α(2A) adrenoceptor
National Category
Physiology Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-73421 (URN)10.1016/j.cellsig.2019.03.019 (DOI)000468251000010 ()30926386 (PubMedID)2-s2.0-85063486315 (Scopus ID)
Funder
AFA Insurance, 130275Knowledge Foundation, 20150240
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-06-19Bibliographically approved
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