PMID- 33762943
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210326
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 12
DP  - 2021
TI  - Inhibition of Autophagy Prevents Panax Notoginseng Saponins (PNS) Protection on 
      Cardiac Myocytes Against Endoplasmic Reticulum (ER) Stress-Induced Mitochondrial 
      Injury, Ca(2+) Homeostasis and Associated Apoptosis.
PG  - 620812
LID - 10.3389/fphar.2021.620812 [doi]
LID - 620812
AB  - Endoplasmic reticulum (ER) stress is often closely linked to autophagy, hypoxia 
      signaling, mitochondrial biogenesis and reactive oxygen species (ROS) responses. 
      Understanding the interaction between ER stress, mitochondrial function and 
      autophagy is of great importance to provide new mechanisms for the pathology, 
      prevention and treatment of cardiovascular diseases. Our previous study has 
      reported that Panax notoginseng saponins (PNS) protection against thapsigargin 
      (TG)-induced ER stress response and associated cell apoptosis in cardiac myocytes 
      is calcium dependent and mediated by ER Ca(2+) release through RyR(2). However, 
      whether its protection upon ER stress and associated apoptosis is related to 
      mitochondrial function and autophagy remains largely unknown. Here, we 
      investigated the roles of PNS played in TG-induced mitochondrial function, ROS 
      accumulation and autophagy. We also assessed its effects on Ca(2+) homeostasis, 
      ER stress response and associated cell death in the presence of autophagy 
      inhibition. PNS-pretreated primary cultured neonatal rat cardiomyocytes were 
      stimulated with TG to induce ER stress response. Mitochondrial potential (Deltapsim) 
      was measured by JC-1. The general and mitochondrial ROS were measured by DCFH-DA 
      and MitoSOX Red, respectively. Autophagy was evaluated by immunofluorescence of 
      LC3, and immunoblots of LC3, p62, ATG7 and PINK1. In addition, mRFP-GFP-LC3 
      labeling was used to assess the autophagic influx. SiATG7 transfected H9c2 cells 
      were generated to inhibit autophagy. Cytosolic and ER Ca(2+) dynamics were 
      investigated by calcium imaging. RyR(2) oxidation was tested by oxyblot. Cell 
      viability was examined by TUNEL assay. ER stress response and cell apoptosis were 
      detected by immunoblots of BiP, CHOP, Cleaved Caspase-3 and Caspase-12. The 
      results demonstrated that firstly, PNS protects against TG-induced mitochondrial 
      injury and ROS accumulation. Secondly, PNS enhances autophagy in TG-induced 
      cardiac myocytes. Thirdly, inhibition of autophagy diminishes PNS prevention of 
      TG-induced mitochondrial injury, ROS accumulation and disruption of Ca(2+) 
      homeostasis. Last but not least, inhibition of autophagy abolishes PNS protection 
      against TG-induced ER stress response and associated apoptosis. In summary, PNS 
      protection against ER stress response and associated apoptosis is related to the 
      regulation of mitochondrial injury and ROS overproduction via modulation of 
      autophagy. These data provide new insights for molecular mechanisms of PNS as a 
      potential preventive approach to the management of cardiovascular diseases.
CI  - Copyright (c) 2021 Chen, Li, Bai, Xiao, Shangguan, Zhang, Zhang, Wang and Liu.
FAU - Chen, Jun
AU  - Chen J
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Li, Li
AU  - Li L
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Bai, Xueyang
AU  - Bai X
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Xiao, Lili
AU  - Xiao L
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Shangguan, Jiahong
AU  - Shangguan J
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Zhang, Wenjing
AU  - Zhang W
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Zhang, Xiangqin
AU  - Zhang X
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Wang, Shen
AU  - Wang S
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Liu, Gangqiong
AU  - Liu G
AD  - Vasculocardiology Department, the First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20210308
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC7982947
OTO - NOTNLM
OT  - Ca2+ homeostasis
OT  - ER stress
OT  - PNS
OT  - ROS
OT  - RyR2 oxidation
OT  - apoptosis
OT  - autophagy
OT  - mitochondrial injury
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/03/26 06:00
MHDA- 2021/03/26 06:01
PMCR- 2021/03/08
CRDT- 2021/03/25 06:26
PHST- 2020/11/04 00:00 [received]
PHST- 2021/01/18 00:00 [accepted]
PHST- 2021/03/25 06:26 [entrez]
PHST- 2021/03/26 06:00 [pubmed]
PHST- 2021/03/26 06:01 [medline]
PHST- 2021/03/08 00:00 [pmc-release]
AID - 620812 [pii]
AID - 10.3389/fphar.2021.620812 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Mar 8;12:620812. doi: 10.3389/fphar.2021.620812. 
      eCollection 2021.