Magnus Grenegård

RESEARCH

Uncontrolled platelet activation represents the most dramatic phase of atherosclerosis, resulting in massive platelet aggregation, vessel occlusion and infarction. Blood platelets are consequently the number one killer of the human population. My research focuses on platelet activation in hemostasis and thrombosis as well as platelets contribution to inflammation, atherosclerosis, and tissue remodeling. The principle aim of the research is to increase the current knowledge of platelets from molecular, physiological and pathological perspectives together with a strong pharmacological research profile. The research activities are necessarily emphasized on specific (but integrated) areas as listed below.

Cross-talk between platelets and the vessel wall

Particular emphasis has been directed towards the role of endothelium-derived nitric oxide (NO), prostaglandin I2 (PGI2), and adenosine in taming of human blood platelets. It has been shown by us and others that concomitant exposure of platelets to NO and adenosine/PGI2 provokes a strong, synergistic inhibition of human platelets. These findings most likely reflect the importance of a functional and health endothelium to keep circulating platelets in a dynamic resting state. From pharmacological perspectives, it would be a great progress to utilize the power of NO and PGI2 to control misdirected platelet activation. Ongoing research aims to identify new molecular targets for NO-releasing drugs and reveal more precise mechanisms by which NO combined with adenosine/PGI2 suppress human platelets.

Connection between primary and secondary hemostasis

This research area is highlighting on specific mechanisms underlying coagulation factor IIa (thrombin)-induced platelet activation. Much attention has been addressed towards the relative role played by the thrombin receptor subtypes designated PAR1 and PAR4. These receptors are co-expressed on the surface of platelets, share the same ligand and initiate identical signal transduction pathways. Current working hypothesis is that there must be physiological reasons for receptor co-expression and differences should be possible to discover. Our recent findings describe the mechanism behind PAR1 desensitization and subsequent “re-sensitization”. In sharp contrast to PAR1, the receptor PAR4 lacks the ability of undergoing receptor desensitization. On the other hand, PAR4 signaling rapidly normalize platelet responsiveness to PAR1 activation. Co-expression may thus be crucial in maintaining thrombin receptors in active states. Furthermore, we also found that the well-known cross-talk between the stress hormone adrenaline and thrombin is highly dependent on PAR4 but not PAR1. This implies that PAR4 may be more significant in platelet activation associated with pathophysiological stress reactions. 

Link between primary hemostasis and inflammation

The complex interplay between platelets and neutrophils has been thoroughly investigated in terms of mechanisms causing altered behavior of the two cell types. Furthermore, our research has revealed previous unknown mechanisms by which the acute-phase reactant alpha1-acid-glycoprotein modulates neutrophils' and platelets' responses. Another area of research is the ongoing evaluation of platelet as a highly “mitogenic” cell type. It is well established that platelets release a large number of soluble growth factors. However, we have shown that platelet membranes also possess pronounced pro-proliferative activity, which may involve interaction with extracellular matrix components.

Key publications

Protease-activated receptor 1 (PAR1) signaling desensitization is counteracted via PAR4 signalling in human platelets. Biochem J. 2011.

Alpha 1-acid glycoprotein (AGP)-induced platelet shape change involves the Rho/Rho kinase signalling pathway. Thromb & Haemost. 2009.

The ATP-gated purinergic P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine. J Biol Chem. 2008.

The acute-phase protein alpha1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (Siglecs). FASEB J. 2007.

Magnus Grenegårds publications in DIVA (publication database)