Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity

Silvio Antoniak; Kohei Tatsumi; Clare M Schmedes; Steven P Grover; Rafal Pawlinski; Nigel Mackman

doi:10.1016/j.yjmcc.2018.08.008

Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity

J Mol Cell Cardiol. 2018 Sep:122:80-87. doi: 10.1016/j.yjmcc.2018.08.008. Epub 2018 Aug 10.

Authors

Silvio Antoniak¹, Kohei Tatsumi², Clare M Schmedes³, Steven P Grover³, Rafal Pawlinski³, Nigel Mackman³

Affiliations

¹ Department of Medicine, Thrombosis and Hemostasis Program, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, United States; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: antoniak@email.unc.edu.
² Department of Medicine, Thrombosis and Hemostasis Program, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, United States; Department of Physiology and Regenerative Medicine, Kindai University, Faculty of Medicine, Osaka-sayama, Osaka, Japan.
³ Department of Medicine, Thrombosis and Hemostasis Program, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, United States.

Abstract

Objective: The anti-cancer anthracycline drug Doxorubicin (Dox) causes cardiotoxicity. We investigated the role of protease-activated receptor 1 (PAR-1) in Dox-induced cardiotoxicity.

Methods and results: In vitro experiments revealed that PAR-1 enhanced Dox-induced mitochondrial dysfunction, reactive oxygen species and cell death of cardiac myocytes and cardiac fibroblasts. The contribution of PAR-1 to Dox-induced cardiotoxicity was investigated by subjecting PAR-1^-/- mice and PAR-1^+/+ mice to acute and chronic exposure to Dox. Heart function was measured by echocardiography. PAR-1^-/- mice exhibited significant less cardiac injury and dysfunction compared to PAR-1^+/+ mice after acute and chronic Dox administration. PAR-1^-/- mice had reduced levels of nitrotyrosine, apoptosis and inflammation in their heart compared to PAR-1^+/+ mice. Furthermore, inhibition of PAR-1 in wild-type mice with vorapaxar significantly reduced the acute Dox-induced cardiotoxicity.

Conclusion: Our results indicate that activation of PAR-1 contributes to Dox-induced cardiotoxicity. Inhibition of PAR-1 may be a new approach to reduce Dox-induced cardiotoxicity in cancer patients.

Keywords: Doxorubicin; Heart failure; Protease-activated receptor 1; Vorapaxar.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
Antibiotics, Antineoplastic / adverse effects*
Apoptosis / drug effects
Cardiotoxicity / etiology*
Cardiotoxicity / metabolism*
Cell Membrane Permeability / drug effects
Cell Survival / drug effects
Doxorubicin / adverse effects*
Echocardiography
Fibroblasts / metabolism
Heart Injuries / metabolism
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Inbred C57BL
Myocardium / cytology
Myocytes, Cardiac / metabolism
Oxidative Stress / drug effects
Rats
Reactive Oxygen Species / metabolism
Receptor, PAR-1 / metabolism*

Substances

Antibiotics, Antineoplastic
Reactive Oxygen Species
Receptor, PAR-1
Doxorubicin

Abstract

Publication types

MeSH terms

Substances

Grants and funding