CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress‑associated apoptotic pathways during ischemia/reperfusion

Liu,Chong; Li,Huanming; Zheng,Huishuang; Zhai,Meili; Lu,Fanghao; Dong,Shiyun; Fang,Tao; Zhang,Weihua

doi:10.3892/ijmm.2019.4255

CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress‑associated apoptotic pathways during ischemia/reperfusion

Authors:
- Chong Liu
- Huanming Li
- Huishuang Zheng
- Meili Zhai
- Fanghao Lu
- Shiyun Dong
- Tao Fang
- Weihua Zhang
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Affiliations: Department of Anesthesiology, Central Laboratory, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin 300140, P.R. China, Department of Cardiology, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin 300140, P.R. China, Department of Pathology, Haiyang Renmin Hospital, Haiyang, Shandong 265100, P.R. China, Department of Anesthesiology, Tianjin Central Hospital of Gynecology Obstetrics, Central Gynecology Obstetrics Hospital of Nankai University, Tianjin 300052, P.R. China, Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Central Laboratory, Tianjin 4th Centre Hospital, The Fourth Central Hospital Affiliated to Nankai University, Tianjin 300140, P.R. China
Published online on: June 24, 2019 https://doi.org/10.3892/ijmm.2019.4255
Pages: 1117-1126

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Abstract

Endoplasmic reticulum (ER) stress can be activated by ischemia/reperfusion (I/R) injury in cardiomyocytes. Persistent ER stress, with an increase in intracellular Ca2+ ([Ca2+]i) concentration, leads to apoptosis. Protein kinase C (PKC) has a key role in myocardial damage by elevation of [Ca2+]i. The calcium‑sensing receptor (CaSR), a G protein‑coupled receptor, can increase the release of [Ca2+]i from the ER through the inositol triphosphate receptor (IP3R). Intracellular calcium overload has been demonstrated to cause cardiac myocyte apoptosis during I/R. However, the associations between PKC, CaSR and ER stress are not clear. The present study examined the hypothesis that activation of PKCδ by CaSR participates in ER stress‑associated apoptotic pathways within myocardial I/R. Rat hearts were subjected to 30 min of ischemia in vivo, followed by reperfusion for 120 min. GdCl3 (a CaSR activator) was used to elevate the intracellular Ca2+ concentration, but the Ca2+ concentration in the ER was significantly decreased during I/R. Following exposure to GdCl3, expression levels of CaSR, glucose‑regulated protein 78 (GRP78), Caspase‑12, phosphorylated JNK and Caspase‑3 were increased, and the ratios of apoptotic myocardial cells were significantly increased. By contrast, following exposure to rottlerin, a PKCδ inhibitor, the expression levels of these proteins and the ratio of apoptotic myocardial cells were significantly reduced. The present study also demonstrated that PKCδ translocated into the ER to induce an ER stress response and participate in the ER stress‑related apoptosis pathway. These results confirmed that CaSR activated PKCδ to induce cardiomyocyte apoptosis through ER stress‑associated apoptotic pathways during I/R in vivo.

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