Vismodegib receptor This study showed that ER redox disturba
This study showed that ER-redox disturbance-associated ER stress is linked to cytoplasmic chaperone signaling, including HSP90 stability and its client protein, eNOS. The highly increased PERK and IRE-1α lead to dissociation with the chaperone protein, thereby decreasing HSP90 stability (Fig. 5B). Similarly, it has been suggested that eNOS is folded with the assistance of cytoplasmic chaperonic proteins, including HSP90, and that the association of eNOS with HSP90 (activator of eNOS) and fluctuation of HSP90 expression can alter eNOS function . The decreased interaction between HSP90 and eNOS was also shown in aging endothelial Vismodegib receptor (Fig. 5C). It has been reported that HSP90 decreases as aging progresses and with an increase in ER stress , . Out of three ER stress markers, two (IRE1α and PERK) are associated with HSP90 and are required for protein stability . As a result of HSP90 decrease, deactivation of eNOS is thought to be induced, indicating that aging-induced ER stress causes the phosphorylation of IRE1α and PERK, which are probably linked to the decreased association of HSP90 through instability.
Through ER stress and Nox4 inhibition approaches, eNOS uncoupling and its related ER stress signaling were established in a relation with HSP90 stability. eNOS uncoupling, the interaction between Nox4 and PDI and its subsequent redox imbalance and ER stress, as well as the linked cytoplasmic chaperone protein characteristics such as decreased HSP90 stability and its dissociated eNOS were shown to be effectively controlled (Fig. 7, Fig. 8). In HUVEC, Nox4 is mainly expressed among Nox family proteins , so GKT137831 has been applied as a Nox4 inhibitor in the HUVEC-based study. Whereas the ER stress inhibitors or the Nox4 inhibitor slightly affect NO release and eNOS Ser1177 phosphorylation, the cytoplasmic ROS scavenger NAC did not recover the association of HSP90 with eNOS and coupling of eNOS . These data indicate that the intra-ER O2--associated redox imbalance and it resultant ER stress are probably the main contributors to eNOS uncoupling.
Conflict of interest
Acknowledgments This research was supported by the National Research Foundation (2015R1A2A1A13001849) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A01005971). This work was partly supported by the Korea Healthcare Technology R&D Project (A121931), Ministry for Health and Welfare, Republic of Korea.
Introduction Peroxidative injury dominated cardiac ischemia/reperfusion injury for a large extent. The excessive production of Reactive oxygen species (ROS) influences mitochondrial electron transport chain, contributing to disorder of energy metabolism and ATP production . In heart, ROS activates mitochondrial permeable transition pore (mPTP) opening, impairs cardiac contractile and leads to cellular apoptosis or necrosis. It is emergency to find an effective pharmacological intervention or compound as the ROS scavenger . Piceatannol, a polyphenol compound derived from grapes and wine shows great antioxidant activity to scavenge free radicals . Lots of researches focus on the effects of piceatannol on cancer cells, like A549, a non-small cell lung cancer line shows piceatannol increases cell apoptosis by enhancing expressions of proapoptotic proteins, Bad and Bak . Additional studies indicate that piceatannol can inhibit cell proliferation by arresting cell cycle in G0 and G1 phases in liver cancer cells or leukemic cells . Hyo Jin Kim and his colleagues investigate the cerebral protective effects of piceatannol in hydrogen peroxide-induced PC12 cells. Piceatannol significantly reduced ROS production, cytotoxicity and cellular apoptosis. It further suppresses Bcl protein downregulation and caspase-3 and -8 activations in JNK-mediated pathways. . Further studies indicate piceatannol can prevent heart from hypercholesterolemia, cardiac arrhythmia, monocyte-endothelial cell adhesion and inflammation .