A Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction
Rationale: Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure.
Objective: We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction.
Methods and Results: We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6 (ATF6), in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of ATF6, including X-box binding protein 1 (XBP1). The decreased levels of XBP1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein (GRP) 78, which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of GRP78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin.
Conclusions: Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone GRP78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of GRP78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.
- Received September 29, 2015.
- Revision received January 25, 2016.
- Accepted January 29, 2016.