Dr Simon Calaminus S.Calaminus@hull.ac.uk
Senior Lecturer
Effect of hypoxia on prostacyclin-mediated inhibition of platelet function
People Involved
Dr Giordano Pula G.Pula@hull.ac.uk
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 |
|---|---|
| Value | £110,353.00 |
| Project Dates | Jan 1, 2023 - Dec 31, 2025 |
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