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Heparin and heparin...
Heparin and heparin proteoglycan-mimetics activate platelets via PEAR1 and PI3K beta
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- Kardeby, Caroline (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.;Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands, England.
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- Evans, Alice (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Campos, Joana (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Al-Wahaibi, Afraa Moosa (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Smith, Christopher W. (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Slater, Alexandre (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Martin, Eleyna M. (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Severin, Sonia (author)
- INSERM U1297, Toulouse, France.;Paul Sabatier Univ, Inst Cardiovasc & Metab Dis, Toulouse, France.
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- Brill, Alexander (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.
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- Pejler, Gunnar (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Sun, Yi (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.;Univ Birmingham, Ctr Membrane Prot & Nottingham, Midlands, England.;Univ Nottingham, Midlands, England.
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- Watson, Steve P. (author)
- Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England.;Univ Birmingham, Ctr Membrane Prot & Nottingham, Midlands, England.;Univ Nottingham, Midlands, England.
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Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England;Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands, England. Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, England. (creator_code:org_t)
- Elsevier, 2023
- 2023
- English.
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In: Journal of Thrombosis and Haemostasis. - : Elsevier. - 1538-7933 .- 1538-7836. ; 21:1, s. 101-116
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Abstract
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- Background: Platelet endothelial aggregation receptor 1 (PEAR1) is a singletransmembrane orphan receptor primarily expressed on platelets and endothelial cells. Genetic variants of PEAR1 have repeatedly and independently been identified to be associated with cardiovascular diseases, including coronary artery disease.Objectives: We have identified sulfated fucoidans and their mimetics as ligands for PEAR1 and proposed that its endogenous ligand is a sulfated proteoglycan. The aim of this study was to test this hypothesis.Methods: A heparin proteoglycan-mimetic (HPGM) was created by linking unfractionated heparin (UFH) to albumin. The ability of the HPGM, UFH and selectively desulfated heparins to stimulate platelet aggregation and protein phosphorylation was investigated. Nanobodies against the 12th to 13th epidermal growth factor-like repeat of PEAR1 and phosphoinositide 3-kinase (PI3K) isoform-selective inhibitors were tested for the inhibition of platelet activation.Results: We show that HPGM, heparin conjugated to an albumin protein core, stimulates aggregation and phosphorylation of PEAR1 in washed platelets. Platelet aggregation was abolished by an anti-PEAR1 nanobody, Nb138. UFH stimulated platelet aggregation in washed platelets, but desulfated UFH did not. Furthermore, HPGM, but not UFH, stimulated maximal aggregation in platelet-rich plasma. However, both HPGM and UFH increased integrin alpha IIb(33 activation in whole blood. By using PI3K isoform-selective inhibitors, we show that PEAR1 activates PI3K(3, leading to Akt phosphorylation.Conclusion: Our findings reveal that PEAR1 is a receptor for heparin and HPGM and that PI3K(3 is a key signaling molecule downstream of PEAR1 in platelets. These findings may have important implications for our understanding of the role of PEAR1 in cardiovascular disease.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- Fucoidan glycosaminoglycan polysaccharides signal transduction sulfates
Publication and Content Type
- ref (subject category)
- art (subject category)
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Kardeby, Carolin ...
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Evans, Alice
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Campos, Joana
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Al-Wahaibi, Afra ...
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Smith, Christoph ...
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Slater, Alexandr ...
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Martin, Eleyna M ...
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Severin, Sonia
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Brill, Alexander
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Pejler, Gunnar
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Sun, Yi
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Watson, Steve P.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
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Uppsala University