PMID- 34943000
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220113
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 10
IP  - 12
DP  - 2021 Nov 26
TI  - Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the 
      Development of Doxorubicin-Induced Cardiomyopathy.
LID - 10.3390/antiox10121897 [doi]
LID - 1897
AB  - Doxorubicin (Dox) is known to cause heart failure in some cancer patients. 
      Despite extensive studies over the past half century, the subcellular basis of 
      Dox-induced cardiomyopathy (DIC) is still elusive. Earlier, we suggested that Dox 
      causes a delayed activation of unfolded protein response (UPR) which may promote 
      mitochondrial Bax activity leading to cardiomyocyte death. As a follow up, using 
      NO donor, S-Nitroso-N-acetyl-d,l-penicillamine (SNAP), and/or NOS inhibitor, 
      N(omega)-nitro-L-arginine methyl ester (L-NAME), we now show that endoplasmic 
      reticulum (ER) stress promotes inflammation through iNOS/NO-induced TLR2 
      activation. In vivo Dox treatment increased mitochondrial iNOS to promote ER 
      stress as there was an increase in Bip (Grp78) response, proapoptotic CHOP 
      (DDIT3) and ER-mediated Caspase 12 activation. Increased iNOS activity is 
      associated with an increase in TLR2 and TNF-alpha receptor associated factor 2 
      (TRAF2). These two together with NF-kappaB p105/50 expression and a synergistic 
      support through ER stress, promote inflammatory response in the myocardium 
      leading to cell death and ultimately fostering DIC conditions. In the presence of 
      NOS inhibitor, such detrimental effects of Dox were inhibited, suggesting iNOS/NO 
      as key mediators of Dox-induced inflammatory as well as apoptotic responses.
FAU - Bagchi, Ashim K
AU  - Bagchi AK
AD  - St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and 
      Pathophysiology, Institute of Cardiovascular Sciences, University of Manitoba, 
      Winnipeg, MB R2H 2A6, Canada.
FAU - Malik, Akshi
AU  - Malik A
AD  - St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and 
      Pathophysiology, Institute of Cardiovascular Sciences, University of Manitoba, 
      Winnipeg, MB R2H 2A6, Canada.
FAU - Akolkar, Gauri
AU  - Akolkar G
AD  - Cardio-Renal Division, Therapeutic Products Directorate, Ottawa, ON K1A 0K9, 
      Canada.
FAU - Jassal, Davinder S
AU  - Jassal DS
AD  - St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and 
      Pathophysiology, Institute of Cardiovascular Sciences, University of Manitoba, 
      Winnipeg, MB R2H 2A6, Canada.
AD  - Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health 
      Sciences, University of Manitoba, Winnipeg, MB R2H 2A6, Canada.
FAU - Singal, Pawan K
AU  - Singal PK
AD  - St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and 
      Pathophysiology, Institute of Cardiovascular Sciences, University of Manitoba, 
      Winnipeg, MB R2H 2A6, Canada.
LA  - eng
GR  - n/a/Heart and Stroke Foundation/
GR  - n/a/Molson Women's Heart Health Grant/
PT  - Journal Article
DEP - 20211126
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC8750247
OTO - NOTNLM
OT  - Dox-induced cardiomyopathy
OT  - ER stress
OT  - Toll-like receptor 2
OT  - apoptosis
OT  - inducible nitric oxide synthase
COIS- Authors declare no conflict of interest.
EDAT- 2021/12/25 06:00
MHDA- 2021/12/25 06:01
PMCR- 2021/11/26
CRDT- 2021/12/24 01:01
PHST- 2021/10/19 00:00 [received]
PHST- 2021/11/18 00:00 [revised]
PHST- 2021/11/23 00:00 [accepted]
PHST- 2021/12/24 01:01 [entrez]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2021/12/25 06:01 [medline]
PHST- 2021/11/26 00:00 [pmc-release]
AID - antiox10121897 [pii]
AID - antioxidants-10-01897 [pii]
AID - 10.3390/antiox10121897 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2021 Nov 26;10(12):1897. doi: 10.3390/antiox10121897.