Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction

Abstract

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, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 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 glucose-regulated protein 78 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 glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 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.

A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

“…Whereas ER stress is further activated in the GBT0411 mutant, its activation is suppressed by the cardiac-specific dnajb6b(L) transgene (Figure 4B). Consistent with the cardioprotective effects of sodium phenylbutyrate (PBA), a chemical chaperone that inhibits ER stress in DOX-induced cardiac dysfunction in mice (24), we found that PBA treatment could decrease the fish mortality rate in both WT and GBT0411 mutant after DOX injection (Figure 4C). …”

A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

“…10,29 In line with these studies, our data demonstrated that BAA treatment significantly inhibited Dox-induced ER stress biomarkers (GRP78, p-eIf2⍺) upregulation and the activation of the JNK pathway, and reduced cell injury in H9c2 cells. ER stress response is a cellular process that is triggered by various stress conditions that can result in the accumulation of misfolded or unfolded proteins in the ER lumen.…”

“…4 The incidence of cardiac events associated with Dox treatment in patients with cancer is estimated to be between 10% and 25%. 10 To overcome Dox-induced cardiotoxicity, combination therapies with cardioprotective agents to improve cancer treatment programs have been a topic of great interest. 5 The cardiotoxicity-induced by Dox has greatly limited its clinical application.…”

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

“…4PB is an epigenetic modulator that increases cellular functional coupling between 2 cardiomyocytes (unpublished data), 2 myofibroblasts or between a cardiomyocyte and myofibroblast. Among the nonepigenetic effects of 4PB is its recognized action as a chemical chaperone, which can reduce endoplasmic reticulum stress and can attenuate the unfolded protein response (50,51). Better folding and improved trafficking to the membrane can give rise to better and more stable (low dynamism) electrical coupling even if Cx43 transcription is not significantly changed, which is probably the case here.…”