Protease-activated receptor 1 activation enhances doxorubicin-induced cardiotoxicity. (September 2018)

• Record Type: Journal Article
• Authors: Antoniak, Silvio; Tatsumi, Kohei; Schmedes, Clare M.; Grover, Steven P.; Pawlinski, Rafal; Mackman, Nigel
• Is Part Of: Journal of molecular and cellular cardiology. Volume 122(2018)
• Page Start: 80
• Page End: 87
• Publication Date: 2018-09
• Subjects: Protease-activated receptor 1 -- Doxorubicin -- Heart failure -- Vorapaxar; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.08.008
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: Protease-activated receptor 1 (PAR-1) contributes to doxorubicin cardiotoxicity. PAR-1 activation increases doxorubicin-induced oxidative stress and apoptosis. PAR-1 activation enhances doxorubicin-mediated cell death of cardiac cells. PAR-1 −/− mice are protected against doxorubicin-induced cardiotoxicity. Vorapaxar protects against doxorubicin-induced heart failure.