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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
Eriksson, L. A., Sirsjö, A. & Strid, Å. (2019). Tetrazole derivatives as cytochrome p450 inhibitors. us US20190040020A1.
Open this publication in new window or tab >>Tetrazole derivatives as cytochrome p450 inhibitors
2019 (English)Patent (Other (popular science, discussion, etc.))
Abstract [en]

According to the invention there is provided a compound of formula I, wherein Rand Rhave meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.

National Category
Basic Medicine Pharmaceutical Sciences Medicinal Chemistry Cell and Molecular Biology Chemical Sciences Theoretical Chemistry Physical Chemistry Biochemistry and Molecular Biology Biophysics
Identifiers
urn:nbn:se:oru:diva-78131 (URN)
Patent
US US20190040020A1
Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved
Zegeye, M. M., Lindkvist, M., Fälker, K., Kumawat, A. K., Paramel Varghese, G., Grenegård, M., . . . Ljungberg, L. U. (2018). Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Communication and Signaling, 16(1), Article ID 55.
Open this publication in new window or tab >>Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells
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2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.

METHODS: In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).

RESULTS: We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.

CONCLUSIONS: Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Endothelium, HUVECs, Interleukin-6 signaling, Monocyte chemoattractant Protein-1, Pro-inflammatory cytokines
National Category
Cell and Molecular Biology
Research subject
Physical Education and Sport Pedagogy; Physical Education and Sport Pedagogy
Identifiers
urn:nbn:se:oru:diva-68803 (URN)10.1186/s12964-018-0268-4 (DOI)000443839900001 ()30185178 (PubMedID)2-s2.0-85053157310 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

Längmanska Foundation  

Foundation for Old Servants (Stiftelsen Gamla Tjänarinnor)  

Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2019-03-26Bibliographically approved
Fransén, K., Paramel Varghese, G., Jansson, J., Eriksson, P. & Sirsjö, A. (2016). Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease. In: : . Paper presented at Miami Winter symposium 2016, Miami, Florida, USA, 24-27 Jan., 2016.
Open this publication in new window or tab >>Molecular genetic aspects of the NLRP3 inflammasome in cardiovascular disease
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2016 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-66012 (URN)
Conference
Miami Winter symposium 2016, Miami, Florida, USA, 24-27 Jan., 2016
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-23Bibliographically approved
Paramel Varghese, G., Folkersen, L., Strawbridge, R. J., Halvorsen, B., Yndestad, A., Ranheim, T., . . . Sirsjö, A. (2016). NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 5(5), Article ID e003031.
Open this publication in new window or tab >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
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2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 5, article id e003031Article in journal (Refereed) Published
Abstract [en]

Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.

Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.

Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016
Keywords
Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:oru:diva-50441 (URN)10.1161/JAHA.115.003031 (DOI)000386711200020 ()27207962 (PubMedID)
Funder
Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
Note

Funding Agencies:

Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC) Linnaeus Center8703

Foundation for Strategic Research, Uppdrag Besegra Stroke P581/2011-123

Strategic Cardiovascular Programs of Karolinska Institutet, Stockholm County Council ALF 20110279

Örebro University

Sigurd and Elsa Goljes Foundation

Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2018-09-12Bibliographically approved
Zhang, B., Sirsjö, A., Khalaf, H. & Bengtsson, T. (2016). Transcriptional profiling of human smooth muscle cells infected with gingipain and fimbriae mutants of Porphyromonas gingivalis. Scientific Reports, 6, Article ID 21911.
Open this publication in new window or tab >>Transcriptional profiling of human smooth muscle cells infected with gingipain and fimbriae mutants of Porphyromonas gingivalis
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21911Article in journal (Refereed) Published
Abstract [en]

Porphyromonas gingivalis (P. gingivalis) is considered to be involved in the development of atherosclerosis. However, the role of different virulence factors produced by P. gingivalis in this process is still uncertain. The aim of this study was to investigate the transcriptional profiling of human aortic smooth muscle cells (AoSMCs) infected with wild type, gingipain mutants or fimbriae mutants of P. gingivalis. AoSMCs were exposed to wild type (W50 and 381), gingipain mutants (E8 and K1A), or fimbriae mutants (DPG-3 and KRX-178) of P. gingivalis. We observed that wild type P. gingivalis changes the expression of a considerable larger number of genes in AoSMCs compare to gingipain and fimbriae mutants, respectively. The results from pathway analysis revealed that the common differentially expressed genes for AoSMCs infected by 3 different wild type P. gingivalis strains were enriched in pathways of cancer, cytokine-cytokine receptor interaction, regulation of the actin cytoskeleton, focal adhesion, and MAPK signaling pathway. Disease ontology analysis showed that various strains of P. gingivalis were associated with different disease profilings. Our results suggest that gingipains and fimbriae, especially arginine-specific gingipain, produced by P. gingivalis play important roles in the association between periodontitis and other inflammatory diseases, including atherosclerosis.

Place, publisher, year, edition, pages
London United Kingdom: Nature Publishing Group, 2016
National Category
Cell and Molecular Biology
Research subject
Cell Research
Identifiers
urn:nbn:se:oru:diva-49361 (URN)10.1038/srep21911 (DOI)000370717700001 ()26907358 (PubMedID)2-s2.0-84959377942 (Scopus ID)
Funder
Swedish Heart Lung Foundation, T77414Knowledge Foundation
Note

Funding Agencies:

Foundation of Olle Engkvist

Foundation of Mats Kleberg

Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2018-07-10Bibliographically approved
Zhang, B., Khalaf, H., Sirsjö, A. & Bengtsson, T. (2015). Gingipains from the Periodontal Pathogen Porphyromonas gingivalis Play a Significant Role in Regulation of Angiopoietin 1 and Angiopoietin 2 in Human Aortic Smooth Muscle Cells. Infection and Immunity, 83(11), 4256-4265
Open this publication in new window or tab >>Gingipains from the Periodontal Pathogen Porphyromonas gingivalis Play a Significant Role in Regulation of Angiopoietin 1 and Angiopoietin 2 in Human Aortic Smooth Muscle Cells
2015 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, no 11, p. 4256-4265Article in journal (Refereed) Published
Abstract [en]

Angiopoietin 1 (Angpt1) and angiopoietin 2 (Angpt2) are the ligands of tyrosine kinase (Tie) receptors, and they play important roles in vessel formation and the development of inflammatory diseases, such as atherosclerosis. Porphyromonas gingivalis is a Gram-negative periodontal bacterium that is thought to contribute to the progression of cardiovascular disease. The aim of this study was to investigate the role of P. gingivalis infection in the modulation of Angpt1 and Angpt2 in human aortic smooth muscle cells (AoSMCs). We exposed AoSMCs to wild-type (W50 and 381), gingipain mutant (E8 and K1A), and fimbrial mutant (DPG-3 and KRX-178) P. gingivalis strains and to different concentrations of tumor necrosis factor (TNF). The atherosclerosis risk factor TNF was used as a positive control in this study. We found that P. gingivalis (wild type, K1A, DPG3, and KRX178) and TNF upregulated the expression of Angpt2 and its transcription factor ETS1, respectively, in AoSMCs. In contrast, Angpt1 was inhibited by P. gingivalis and TNF. However, the RgpAB mutant E8 had no effect on the expression of Angpt1, Angpt2, or ETS1 in AoSMCs. The results also showed that ETS1 is critical for P. gingivalis induction of Angpt2. Exposure to Angpt2 protein enhanced the migration of AoSMCs but had no effect on proliferation. This study demonstrates that gingipains are crucial to the ability of P. gingivalis to markedly increase the expressed Angpt2/Angpt1 ratio in AoSMCs, which determines the regulatory role of angiopoietins in angiogenesis and their involvement in the development of atherosclerosis. These findings further support the association between periodontitis and cardiovascular disease.

Place, publisher, year, edition, pages
American Society for Microbiology, 2015
Keywords
Angiopoietin 1, Angiopoietin 2, Smooth Muscle cells, TNF, Periodontitis, Atherosclerosis, Porphyromonas gingivalis
National Category
Cell and Molecular Biology Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:oru:diva-46137 (URN)10.1128/IAI.00498-15 (DOI)000362494000009 ()26283334 (PubMedID)
Funder
Knowledge FoundationSwedish Heart Lung Foundation, T77414
Note

Funding Agencies:

Swedish Research Council for Medicine and Health 2008-2459

Foundation of Olle Engkvist

Foundation of Mats Kleberg

Available from: 2015-10-16 Created: 2015-10-16 Last updated: 2018-01-11Bibliographically approved
Paramel, G., Uporova, L., Halfvarson, J., Sirsjö, A. & Fransén, K. (2015). Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease. Molecular Medicine Reports, 11(6), 4579-4584
Open this publication in new window or tab >>Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease
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2015 (English)In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, no 6, p. 4579-4584Article in journal (Refereed) Published
Abstract [en]

Inflammatory bowel disease (IBD) is the common name for numerous relapsing inflammatory conditions, and is the collective name for Crohn's disease (CD) and ulcerative colitis (UC). The activation of the inflammasome in the pathogenesis of IBD has recently been identified, however the underlying mechanisms remain unclear. An activator of the inflammasome is double-stranded RNA-dependent protein kinase R, also termed EIF2AK2. A genetic alteration in the EIF2AK2 gene has previously been shown to be associated with Alzheimer's disease. The present study genotyped samples from a Swedish cohort of patients with IBD and healthy controls for an EIF2AK2 polymorphism. The rs2254958 polymorphism in the 5'-untranslated region of the EIF2AK2 gene was genotyped by TaqMan® single nucleotide polymorphism genotyping, followed by allelic discrimination. However, no significant association was determined between the rs2254958 polymorphism and the development of IBD, or clinical outcome. In conclusion, the results of the present study suggest that the rs2254958 polymorphism has a limited effect on the onset or progression of IBD.

Keywords
EIF2AK2; Inflammasome; NLRP3; Polymorphism; Protein kinase R; Rs2254958
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-41505 (URN)10.3892/mmr.2015.3236 (DOI)000355497100083 ()25607115 (PubMedID)2-s2.0-84924674689 (Scopus ID)
Funder
Swedish Research Council, 521-2011-2764Magnus Bergvall Foundation
Note

Funding Agencies:

Örebro University (Örebro, Sweden)

Bengt Ihre's Foundation

Nanna Svartz's Foundation

Örebro University Hospital Research Foundation

Örebro County Research Foundation

Swedish Foundation for Gastrointestinal Research

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved
Paramel, G., Sirsjö, A. & Fransén, K. (2015). Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease. Mediators of Inflammation, Article ID 846782.
Open this publication in new window or tab >>Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease
2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 846782Article in journal (Refereed) Published
Abstract [en]

The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

Place, publisher, year, edition, pages
New York: Hindawi Publishing Corporation, 2015
Keywords
NLRP3, inflammasome, polymorphism, CARD8
National Category
Immunology in the medical area
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-42795 (URN)10.1155/2015/846782 (DOI)000350655400001 ()2-s2.0-84924227184 (Scopus ID)
Note

Funding Agencies:

Magnus Bergvalls Foundation

Sigurd and Elsa Goljes Minne (Lindhes Advokatbyrå AB)

Stiftelsen Gamla Tjänarinnor

Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2018-01-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0278-4510

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