Dr Simon Calaminus S.Calaminus@hull.ac.uk
Effect of hypoxia on prostacyclin-mediated inhibition of platelet function
People Involved
Project Description
Tissue hypoxia occurs in multiple cardiovascular and pulmonary conditions that have platelet activation or hyperreactivity, including myocardial infarction, stroke, chronic obstructive pulmonary disease (COPD) and sleep apnoea. However, knowledge on how human platelets function at low oxygen (O2) tension is incomplete. It is currently unknown if hypoxia affects platelet inhibition by endothelial-released prostacyclin (PGI2) and downstream intracellular signalling via cyclic AMP (cAMP) and protein kinase A (PKA). Our pilot data show that at low O2 tension (2%), PGI2 inhibition of platelet spreading on fibrinogen is reduced, and PGI2-induced VASP Ser157 phosphorylation (a PKA activation marker) is transient compared to atmospheric O2 levels (21%). We hypothesise that hypoxia reduces platelet responsiveness to PGI2 by modulating the cAMP/PKA cascade. This studentship will, therefore, characterise in unprecedented detail the effects of hypoxic, venous and arterial O2 levels on healthy donor platelet function and PGI2/cAMP/PKA responsiveness compared to atmospheric O2 (standard laboratory practice). The pathophysiological relevance of our findings will be validated in platelets from coronary artery disease, COPD and sleep apnoea patients. This study will, for the first time, determine how hypoxia attenuates the thromboprotective effect of PGI2/cAMP/PKA, and if targeting this pathway could be a potential antiplatelet strategy in ischaemic disease.
| Status | Project Live |
|---|---|
| Funder(s) | British Heart Foundation |
| Value | £110,353.00 |
| Project Dates | Jan 1, 2023 - Dec 31, 2025 |
You might also like
ThrombiGlow: ‘Smart’ Multimodal Platelet Specific ‘Theranostic’ Drug Delivery Imaging Feb 1, 2017 - Jan 31, 2020
Cardiovascular diseases (CVD) including heart attacks and strokes constitute the leading cause of mortality in the UK. The pathology underlying CVD is called atherothrombosis and is a complex, multi-cellular-inflammatory disorder. Central to this is...
Read More about ThrombiGlow: ‘Smart’ Multimodal Platelet Specific ‘Theranostic’ Drug Delivery Imaging.
Platelet cAMP signalling controls thrombosis through enhanced embolisation Oct 1, 2015 - Sep 30, 2018
The activation of protein kinase A (PKA) by prostacyclin inhibits platelet activation and therefore modulates arterial thrombosis. However, the role of PKA in controlling the stability of pre-existing thrombi is unclear. The stability of thrombi is r...
Read More about Platelet cAMP signalling controls thrombosis through enhanced embolisation.
Is zinc a critical modulator of cyclic nucleotide signalling? Oct 1, 2019 - Dec 31, 2022
inc (Zn2+) deficiency is present in multiple conditions from obesity to cancer. However importantly Zn2+ deficiency can lead to a bleeding phenotype.In this proposal we investigate how Zn2+ is important for the control of platelet cyclic nucleotide...
Read More about Is zinc a critical modulator of cyclic nucleotide signalling?.
TARGETING THE MYOSIN LIGHT CHAIN PHOSPHATASE WITH PEPTIDE DISRUPTORS: A NOVEL ANTIPLATELET THERAPEUTIC APPROACH Jul 3, 2023 - Jul 2, 2026
Platelet activation and thrombus formation play key roles in the pathogenesis of ischaemic cardiovascular diseases, one of the major causes of death in the UK. Many antiplatelet agents have been developed to manage these conditions; however, they are...
Read More about TARGETING THE MYOSIN LIGHT CHAIN PHOSPHATASE WITH PEPTIDE DISRUPTORS: A NOVEL ANTIPLATELET THERAPEUTIC APPROACH.