Statin Therapy Before Percutaneous Coronary Intervention: A Novel Bridge Between Thrombin and Thrombomodulin for Enhanced Cardiovascular Protection

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2025 Feb 24

PMID 39989830

Authors

Zhen Wang

Bin Lai

Xiaoli Shi

Xiaochen Wang

Xiaohong Fang

Yujie Wei

Xiaofeng Wang

Affiliations

Soon will be listed here.

Abstract

Percutaneous coronary intervention administration of statins enhances the thrombin-thrombomodulin (TM) interaction, which is critical for the prevention of post-procedural cardiovascular complications. Atomic force microscopy showed that statins increased the single molecule rupture forces between thrombin and TM, suggesting a strengthened complex. This was supported by surface plasmon resonance, which showed an enhanced binding affinity under the statin treatment. Molecular docking and dynamics simulations revealed that statins can bind to both thrombin and TM, forming stable complexes that facilitate protein C activation. Clinically relevant doses of statins were found to significantly enhance the thrombin-TM interaction, potentially reducing the risk of myocardial infarction and stent thrombosis by augmenting the endothelial anticoagulant properties through the thrombin-TM pathway. By acting as a bridge, statins foster more stable thrombin-TM complexes, supporting endogenous anticoagulant mechanisms and leading to better cardiovascular outcomes.

References

De Cristofaro R, De Candia E, Landolfi R . Effect of high- and low-molecular-weight heparins on thrombin-thrombomodulin interaction and protein C activation. Circulation. 1998; 98(13):1297-301. DOI: 10.1161/01.cir.98.13.1297. View

Lopes R, Hong H, Harskamp R, Bhatt D, Mehran R, Cannon C . Optimal Antithrombotic Regimens for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: An Updated Network Meta-analysis. JAMA Cardiol. 2020; 5(5):582-589. PMC: 7240352. DOI: 10.1001/jamacardio.2019.6175. View

Luo J, Cheng C, Gou L, He L, Zhao L, Zhang Y . Induction of KLF2 by Exercise Activates eNOS to Improve Vasodilatation in Diabetic Mice. Diabetes. 2023; 72(9):1330-1342. DOI: 10.2337/db23-0070. View

Alirezaei T, Sattari H, Irilouzadian R . Significant decrease in plasmad-dimer levels and mean platelet volume after a 3-month treatment with rosuvastatin in patients with venous thromboembolism. Clin Cardiol. 2022; 45(7):717-722. PMC: 9286331. DOI: 10.1002/clc.23833. View

Loeffen R, Godschalk T, van Oerle R, Spronk H, Hackeng C, Ten Berg J . The hypercoagulable profile of patients with stent thrombosis. Heart. 2015; 101(14):1126-32. PMC: 4515992. DOI: 10.1136/heartjnl-2014-306685. View

Siniscalchi C, Basaglia M, Riva M, Meschi M, Meschi T, Castaldo G . Statins Effects on Blood Clotting: A Review. Cells. 2023; 12(23). PMC: 10706238. DOI: 10.3390/cells12232719. View

Galli M, Niccoli G, De Maria G, Brugaletta S, Montone R, Vergallo R . Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction. Nat Rev Cardiol. 2023; 21(5):283-298. DOI: 10.1038/s41569-023-00953-4. View

Feng Y, Roos W . Atomic Force Microscopy: An Introduction. Methods Mol Biol. 2023; 2694:295-316. DOI: 10.1007/978-1-0716-3377-9_14. View

Byrne R, Rossello X, Coughlan J, Barbato E, Berry C, Chieffo A . 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023; 44(38):3720-3826. DOI: 10.1093/eurheartj/ehad191. View

10.

Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis J, Dror R . Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins. 2010; 78(8):1950-8. PMC: 2970904. DOI: 10.1002/prot.22711. View

11.

Hess B, Kutzner C, van der Spoel D, Lindahl E . GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J Chem Theory Comput. 2015; 4(3):435-47. DOI: 10.1021/ct700301q. View

12.

Chen J, Zhou C, Fang W, Yin J, Shi J, Ge J . Identification of endothelial protein C receptor as a novel druggable agonistic target for reendothelialization promotion and thrombosis prevention of eluting stent. Bioact Mater. 2024; 41:485-498. PMC: 11359769. DOI: 10.1016/j.bioactmat.2024.07.028. View

13.

Leon G, Rehill A, Preston R . The protein C pathways. Curr Opin Hematol. 2022; 29(5):251-258. DOI: 10.1097/MOH.0000000000000726. View

14.

Ma W, Yang L, He L . Overview of the detection methods for equilibrium dissociation constant of drug-receptor interaction. J Pharm Anal. 2018; 8(3):147-152. PMC: 6004624. DOI: 10.1016/j.jpha.2018.05.001. View

15.

Rodrigo R, Retamal C, Schupper D, Vergara-Hernandez D, Saha S, Profumo E . Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin. Molecules. 2022; 27(8). PMC: 9027566. DOI: 10.3390/molecules27082564. View

16.

Kim J, Kim J, Choi D, Lee C, Lee S, Ko Y . Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial. JACC Cardiovasc Interv. 2010; 3(3):332-9. DOI: 10.1016/j.jcin.2009.11.021. View

17.

WAUGH J, Yuksel E, Kuo M, Cifra P, Hilfiker P, Geske R . Thrombomodulin overexpression to limit neointima formation. Circulation. 2000; 102(3):332-7. DOI: 10.1161/01.cir.102.3.332. View

18.

Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G . Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol. 2007; 49(12):1272-8. DOI: 10.1016/j.jacc.2007.02.025. View

19.

Lopes R, de Barros E Silva P, de Andrade Jesuino I, Santucci E, Barbosa L, Damiani L . Timing of Loading Dose of Atorvastatin in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes: Insights From the SECURE-PCI Randomized Clinical Trial. JAMA Cardiol. 2018; 3(11):1113-1118. PMC: 6583055. DOI: 10.1001/jamacardio.2018.3408. View

20.

Randi A, Jones D, Peghaire C, Arachchillage D . Mechanisms regulating heterogeneity of hemostatic gene expression in endothelial cells. J Thromb Haemost. 2023; 21(11):3056-3066. DOI: 10.1016/j.jtha.2023.06.024. View