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

Abstract

Endoplasmic reticulum (ER) stress can be activated by ischemia/reperfusion (I/R) injury in cardiomyocytes. Persistent ER stress, with an increase in intracellular ca 2+ ([ca 2+ ]i) concentration, leads to apoptosis. Protein kinase c (PKc) has a key role in myocardial damage by elevation of [ca 2+ ]i. The calcium-sensing receptor (caSR), a G protein-coupled receptor, can increase the release of [ca 2+ ]i from the ER through the inositol triphosphate receptor (IP 3 R). 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. Gdcl 3 (a caSR activator) was used to elevate the intracellular ca 2+ concentration, but the ca 2+ concentration in the ER was significantly decreased during I/R. Following exposure to Gdcl 3 , 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.

Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health

“…This reduced expression of CaSR enhanced the vasodilation of the arteries and regulated the vascular tension and the blood pressure in the rats through the PLC-IP3/cAMP/RAAS pathways [27]. In rats with spontaneous hypertension, AngII also activates CaSR, as well as NLRP3 inflammasome in vSMCs [78].…”

Couplet medicines of leech and centipede granules improve erectile dysfunction via inactivation of the CaSR/PLC/PKC signaling in streptozotocin-induced diabetic rats

“…The CaSR, a PLC sensitive G protein-coupled receptor, can increase the release of [Ca 2+ ]i from the endoplasmic reticulum via the inositol triphosphate receptor (IP3R). Notably, Liu et al demonstrated that CaSR activated PKCδ to induce cardiomyocyte apoptosis during ischemia/reperfusion (I/R) injury [44]. However, the associations between CaSR, PLC, PKCδ, and DMED are not clear.…”

Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury

“…The critical role of DRP1 in this process is illustrated by observations that, in the settings of DRP1 inhibition achieved by knockdown or overexpression of dominant negative mutant forms of the protein, DRP1 docking to the OMM is impaired and release of cytochrome c is prevented or delayed [114,122,123]. Finally, DRP1-mediated fission, and the interaction between DRP1 and Bax/Bak oligomers, also involves mitochondrial-ER contact sites along the OMM [66,69,124,125] (Figure 4), with ER stress and ER-mediated calcium release being sufficient to serve as stimuli for DRP1 recruitment and initiation of Bax/Bak oligomerization and MOMP [66,125]. Taken together, these observations underscore the concept that DRP1 (and DRP recruitment to mitochondria) is at the nexus of mitochondrial quality control, pathologic fission, and apoptotic cell death via the intrinsic pathway.…”

“…For example, Bax/Bak-mediated MOMP has been shown to occur in response to transmission of ER stress to the mitochondria and subsequent sequestration of calcium within the mitochondrial matrix. These hallmarks of apoptosis (i.e., matrix swelling and calcium overload) are, in turn, accompanied by disruption of cristae architecture, loss of mitochondrial membrane potential and OPA1 degradation [66,124,163]. Moreover, putative triggers of MOMP, including Bax/Bak and DRP1, have been shown to regulate cristae morphology by induction of OMA1 and destabilization of OPA1 oligomers-a sequence of events that mobilize cytochrome c release from cristae [156,159].…”