Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure

Mohammed M Jalal; Claire S Whyte; Fraser P Coxon; Nicola J Mutch

doi:10.1080/09537104.2023.2206921

Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure

Mohammed M Jalal, Claire S Whyte, Fraser P Coxon, Nicola J Mutch

Research output: Contribution to journal › Article › peer-review

Abstract

Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P
Plain Language Summary
What is the context?

Statins such as Atorvastatin (ATV) are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol.

The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases.

Prenyl groups provide a membrane anchor that is essential for the correct membrane localization and function of these proteins.

Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins.

Rab27b and Rap1 are small GTPase proteins in platelets that are involved in the secretion of platelet granules and integrin activation.

What is new?

In this study, we found that ATV impairs prenylation of Rab27b and Rap1a and attenuates platelet function.

These effects were partially rescued by GGPP, indicating the involvement of the mevalonate pathway.

Platelet aggregation and degranulation was significantly attenuated by ATV.

The impact of statins on platelet function altered clot formation, structure and contraction generating a clot that was more susceptible to degradation.

What is the impact?

This study demonstrates a novel mechanism whereby statins alter platelet responses and ultimately clot structure and stability.

Original language	English
Article number	2206921
Number of pages	12
Journal	Platelets
Volume	34
Issue number	1
DOIs	https://doi.org/10.1080/09537104.2023.2206921
Publication status	Published - 4 May 2023

Keywords

Fibrin
platelates
Rab27b
statins
thrombosis

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10.1080/09537104.2023.2206921

Jalal_etal_P_Atorvastatin-mediated_inhibition_of_VOR
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@article{5ca9a1b7e7e8456d84d9a0d7a49edc18,

title = "Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure",

abstract = "Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P Plain Language SummaryWhat is the context?Statins such as Atorvastatin (ATV) are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol.The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases.Prenyl groups provide a membrane anchor that is essential for the correct membrane localization and function of these proteins.Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins.Rab27b and Rap1 are small GTPase proteins in platelets that are involved in the secretion of platelet granules and integrin activation.What is new?In this study, we found that ATV impairs prenylation of Rab27b and Rap1a and attenuates platelet function.These effects were partially rescued by GGPP, indicating the involvement of the mevalonate pathway.Platelet aggregation and degranulation was significantly attenuated by ATV.The impact of statins on platelet function altered clot formation, structure and contraction generating a clot that was more susceptible to degradation.What is the impact?This study demonstrates a novel mechanism whereby statins alter platelet responses and ultimately clot structure and stability.",

keywords = "Fibrin, platelates, Rab27b, statins, thrombosis",

author = "Jalal, {Mohammed M} and Whyte, {Claire S} and Coxon, {Fraser P} and Mutch, {Nicola J}",

note = "Acknowledgments The authors thank the Microscopy and Histology Core Facility and the Iain Fraser Cytometry at the University of Aberdeen for excellent advice and use of facilities. The authors thank the Deanship of the Scientific Research at the University of Tabuk for supporting this work. Funding This study was supported by grants from the University of Tabuk, Tabuk, Saudi Arabia (M.M.J & N.J.M) (TBU126) and (S-1440-0311). The material of this manuscript has been formed part of a doctoral dissertation that is available online at the University of Aberdeen. C.S.W and N.J.M are supported by grants from the British Heart Foundation PG/15/82/31721 and PG/20/17/35050 and Tenovus Scotland Grampian, Highlands and Islands G17.03.",

year = "2023",

month = may,

day = "4",

doi = "10.1080/09537104.2023.2206921",

language = "English",

volume = "34",

journal = "Platelets",

issn = "0953-7104",

publisher = "Informa Healthcare",

number = "1",

}

TY - JOUR

T1 - Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure

AU - Jalal, Mohammed M

AU - Whyte, Claire S

AU - Coxon, Fraser P

AU - Mutch, Nicola J

N1 - Acknowledgments The authors thank the Microscopy and Histology Core Facility and the Iain Fraser Cytometry at the University of Aberdeen for excellent advice and use of facilities. The authors thank the Deanship of the Scientific Research at the University of Tabuk for supporting this work. Funding This study was supported by grants from the University of Tabuk, Tabuk, Saudi Arabia (M.M.J & N.J.M) (TBU126) and (S-1440-0311). The material of this manuscript has been formed part of a doctoral dissertation that is available online at the University of Aberdeen. C.S.W and N.J.M are supported by grants from the British Heart Foundation PG/15/82/31721 and PG/20/17/35050 and Tenovus Scotland Grampian, Highlands and Islands G17.03.

PY - 2023/5/4

Y1 - 2023/5/4

N2 - Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P Plain Language SummaryWhat is the context?Statins such as Atorvastatin (ATV) are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol.The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases.Prenyl groups provide a membrane anchor that is essential for the correct membrane localization and function of these proteins.Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins.Rab27b and Rap1 are small GTPase proteins in platelets that are involved in the secretion of platelet granules and integrin activation.What is new?In this study, we found that ATV impairs prenylation of Rab27b and Rap1a and attenuates platelet function.These effects were partially rescued by GGPP, indicating the involvement of the mevalonate pathway.Platelet aggregation and degranulation was significantly attenuated by ATV.The impact of statins on platelet function altered clot formation, structure and contraction generating a clot that was more susceptible to degradation.What is the impact?This study demonstrates a novel mechanism whereby statins alter platelet responses and ultimately clot structure and stability.

AB - Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P Plain Language SummaryWhat is the context?Statins such as Atorvastatin (ATV) are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol.The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases.Prenyl groups provide a membrane anchor that is essential for the correct membrane localization and function of these proteins.Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins.Rab27b and Rap1 are small GTPase proteins in platelets that are involved in the secretion of platelet granules and integrin activation.What is new?In this study, we found that ATV impairs prenylation of Rab27b and Rap1a and attenuates platelet function.These effects were partially rescued by GGPP, indicating the involvement of the mevalonate pathway.Platelet aggregation and degranulation was significantly attenuated by ATV.The impact of statins on platelet function altered clot formation, structure and contraction generating a clot that was more susceptible to degradation.What is the impact?This study demonstrates a novel mechanism whereby statins alter platelet responses and ultimately clot structure and stability.

KW - Fibrin

KW - platelates

KW - Rab27b

KW - statins

KW - thrombosis

U2 - 10.1080/09537104.2023.2206921

DO - 10.1080/09537104.2023.2206921

M3 - Article

C2 - 37139869

VL - 34

JO - Platelets

JF - Platelets

SN - 0953-7104

IS - 1

M1 - 2206921

ER -

Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure

Abstract

Keywords

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