CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during ischemia/reperfusion
CaSR activates PKCδ to induce cardiomyocyte apoptosis via ER stress-associated apoptotic pathways during ischemia/reperfusion
复制标题
CaSR 激活 PKC δ，通过缺血/再灌注期间 ER 应激相关的细胞凋亡途径诱导心肌细胞凋亡
DOI：
10.3892/ijmm.2019.4255
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发表时间：
2019-09-01
影响因子：
5.4
通讯作者：
Zhang, Weihua
中科院分区：
文献类型：
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作者：
Liu, Chong;Li, Huanming;Zhang, Weihua
心肌细胞缺血/再灌注（I/R）损伤可激活内质网应激。持续内质网应激，随着细胞内Ca2+ ([Ca2+]i)浓度的增加，导致细胞凋亡。蛋白激酶C （PKC）在[Ca2+]i升高引起的心肌损伤中起关键作用。钙敏感受体（CaSR）是一种G蛋白偶联受体，可通过肌醇三磷酸受体（IP3R）增加内质网[Ca2+]i的释放。细胞内钙超载已被证明在I/R期间引起心肌细胞凋亡。然而，PKC、CaSR和内质网应激之间的关系尚不清楚。本研究检验了CaSR激活PKC δ参与心肌I/R内内质网应激相关凋亡通路的假设。大鼠心脏在体内缺血30 min，再灌注120 min。使用GdCl3（一种CaSR激活剂）提高细胞内Ca2+浓度，但在I/R期间ER内Ca2+浓度显著降低。GdCl3暴露后，CaSR、葡萄糖调节蛋白78 （GRP78）、Caspase-12、磷酸化JNK和Caspase-3的表达水平升高，心肌细胞凋亡比例显著升高。相比之下，暴露于PKC δ抑制剂rottlerin后，这些蛋白的表达水平和心肌细胞凋亡比例显著降低。本研究还证实PKC δ易位到内质网诱导内质网应激反应，参与内质网应激相关的凋亡通路。这些结果证实，在体内I/R过程中，CaSR激活PKC δ通过内质网应激相关的凋亡途径诱导心肌细胞凋亡。
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 PKC delta 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 PKC delta inhibitor, the expression levels of these proteins and the ratio of apoptotic myocardial cells were significantly reduced. The present study also demonstrated that PKC delta 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 PKC delta to induce cardiomyocyte apoptosis through ER stress-associated apoptotic pathways during I/R in vivo.