Graduate Student Univ of Alberta Faculty of Med Edmonton, Alberta, Canada
Abstract: Cardiovascular disease (CVD) is the leading cause of death worldwide with no cure identified so far, the current clinical treatment method primarily relies on early diagnosis. Activation of the endoplasmic reticulum (ER) stress is associated with CVD or it may be triggered by CVD. Therefore, targeting ER stress signalling is a promising therapeutic direction. We previously showed that in isolated adult mouse cardiomyocytes, IRE1α (the most conserved ER stress sensor) is localized to the junctional sarcoplasmic reticulum (jSR) responsible for the regulation of cardiac excitation-contraction (E-C) coupling. In this study we used mouse embryonic stem (mES) cells with deletion of the IRE1α gene and showed delayed cardiac differentiation with weak beating activities, indicating an important role of IRE1α in cardiac development and cardiomyocyte function. We also discovered that IRE1α is in close proximity with the Cav1.2 (the α subunit of L-type calcium channel) and Cavβ2 (the β subunit of L-type calcium channel) in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. These findings indicate that IRE1α plays a novel role in supporting cardiac E-C coupling through regulating the L-type calcium channel and controlling calcium homeostasis. Nonetheless, IRE1α showed activation in response to thapsigargin and tunicamycin-induced ER stress indicating that IRE1α also plays a canonical role in responding to ER stress in the heart through the IRE1α-XBP1 signalling pathway. Since the dysfunctions of L-type calcium channel and excessive ER stress give rise to cardiac defects, IRE1α may serve a cardioprotective role in the heart as a L-type calcium channel regulator and an ER stress sensor. As the generation of iPSC provides a patient-specific platform for thorough understanding of the CVD pathology, further investigating the mechanism of IRE1α as a component of cardiac E-C coupling, specifically as a regulator of the L-type calcium channel points towards a new direction for CVD drug development.
Funding Source: Canadian Institutes of Health Research (CIHR) China Scholarship Council (CSC)
