Inhibition of Arginine Methylation Impairs Platelet Function.

Alistair James Marsden,Antonia Barry,Neil T Kemp,Barbara-Ann Guinn,Francisco Rivero,Jawad S Khalil,David R J Riley,Pedro Beltran-Alvarez

doi:10.1021/acsptsci.1c00135

Abstract

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to arginine residues in proteins. PRMT inhibitors are novel, promising drugs against cancer that are currently in clinical trials, which include oral administration of the drugs. However, off-target activities of systemically available PRMT inhibitors have not yet been investigated. In this work, we study the relevance of arginine methylation in platelets and investigate the effect of PRMT inhibitors on platelet function and on the expression of relevant platelet receptors. We show that (1) key platelet proteins are modified by arginine methylation; (2) incubation of human platelets with PRMT inhibitors for 4 h results in impaired capacity of platelets to aggregate in response to thrombin and collagen, with IC50 values in the μM range; and (3) treatment with PRMT inhibitors leads to decreased membrane expression and reduced activation of the critical platelet integrin αIIbβ3. Our contribution opens new avenues for research on arginine methylation in platelets, including the repurposing of arginine methylation inhibitors as novel antiplatelet drugs. We also recommend that current and future clinical trials with PRMT inhibitors consider any adverse effects associated with platelet inhibition of these emerging anticancer drugs.

Highlights

Platelets, or thrombocytes, are small anucleate discoid cells of 3 μm in diameter and key components of normal haemostasis.[1]
Arginine methylation (ArgMe) of proteins consists of the transfer of a methyl group (CH3) from S-adenosyl-L-methionine onto the side chain guanidino nitrogen of arginine, in an enzymatic reaction catalysed by protein arginine methyltransferases (PRMTs).[14]
Over the past few years, several groups have begun to identify the set of proteins modified by ArgMe, that is, the arginine methylome, in various cells and tissues,[22, 25,26,27,28] the extent and role of ArgMe in platelets has not yet been investigated

Summary

Introduction

Thrombocytes, are small anucleate discoid cells of 3 μm in diameter and key components of normal haemostasis.[1]. Antiplatelet drugs interfere with mechanisms of platelet activation or aggregation and include aspirin, P2Y12 receptor blockers (such as clopidogrel and ticagrelor) and αIIbβ[3] antagonists.[7] Antiplatelet drugs have gained visibility in the context of the COVID-19 pandemic,[8] because overall 17% of COVID-19 patients suffer from venous thromboembolisms.[9] antiplatelet drugs are widely used in the clinics, there is a subtle balancing act between the desirable antiplatelet effects of therapy in patients and a higher risk of bleeding.[10]. In a normal physiology setting, the premature activation of platelets is inhibited by endogenous substances secreted by endothelial cells, namely prostacyclin (PGI2) and nitric oxide (NO). It is accepted that most of the ArgMe activity in mammalian cells can be attributed to PRMT1.17, 18

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