PMID- 37235521
OWN - NLM
STAT- MEDLINE
DCOM- 20230623
LR  - 20230710
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 325
IP  - 1
DP  - 2023 Jul 1
TI  - Placenta-targeted treatment with nMitoQ prevents an endothelin receptor-A pathway 
      cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.
PG  - H136-H141
LID - 10.1152/ajpheart.00238.2023 [doi]
AB  - Prenatal hypoxia is associated with enhanced susceptibility to cardiac 
      ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms 
      remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that 
      acts via endothelin A (ET(A)) and endothelin B (ET(B)) receptors and is essential 
      in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 
      system in adult offspring possibly contributing to I/R susceptibility. We 
      previously showed that ex vivo application of ET(A) antagonist ABT-627 during I/R 
      prevented the recovery of cardiac function in prenatal hypoxia-exposed males but 
      not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this 
      follow-up study, we examined whether placenta-targeted treatment with a 
      nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic 
      pregnancies could alleviate this hypoxic phenotype observed in adult male 
      offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley 
      rats were exposed to hypoxia (11% O(2)) from gestational days (GD) 15-21 after 
      injection with 100 muL saline or nMitoQ (125 muM) on GD15. Male offspring were aged 
      to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from 
      hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from 
      I/R in the presence of ABT-627 compared with their untreated counterparts where 
      ABT-627 prevented recovery. Cardiac ET(A) levels were increased in males born 
      from hypoxic pregnancies with nMitoQ treatment compared with saline controls 
      (Western blotting). Our data indicate a profound impact of placenta-targeted 
      treatment to prevent an ET(A) receptor cardiac phenotype observed in adult male 
      offspring exposed to hypoxia in utero.NEW & NOTEWORTHY In this follow-up study, 
      we showed a complete lack of recovery from I/R injury after the application of an 
      ET(A) receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in 
      utero while maternal treatment with nMitoQ during prenatal hypoxia exposure 
      prevented this effect. Our data suggest that nMitoQ treatment during hypoxic 
      pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.
FAU - Hula, Nataliia
AU  - Hula N
AUID- ORCID: 0000-0002-4923-6589
AD  - Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Kirschenman, Raven
AU  - Kirschenman R
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Quon, Anita
AU  - Quon A
AUID- ORCID: 0000-0003-2334-4618
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Spaans, Floor
AU  - Spaans F
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Phillips, Tom J
AU  - Phillips TJ
AD  - Dementia Research Institute, Cardiff University, Cardiff, United Kingdom.
FAU - Case, C Patrick
AU  - Case CP
AD  - Musculoskeletal Research Unit, University of Bristol, Bristol, United Kingdom.
FAU - Cooke, Christy-Lynn M
AU  - Cooke CM
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
FAU - Davidge, Sandra T
AU  - Davidge ST
AUID- ORCID: 0000-0002-5559-4905
AD  - Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
AD  - Department of Obstetrics and Gynecology, University of Alberta, Edmonton, 
      Alberta, Canada.
AD  - Women and Children's Health Research Institute, University of Alberta, Edmonton, 
      Alberta, Canada.
LA  - eng
GR  - FS154313/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230526
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Receptors, Endothelin)
RN  - V6D7VK2215 (Atrasentan)
RN  - 0 (Endothelin-1)
SB  - IM
MH  - Pregnancy
MH  - Female
MH  - Rats
MH  - Male
MH  - Animals
MH  - Rats, Sprague-Dawley
MH  - *Receptors, Endothelin
MH  - Atrasentan
MH  - Follow-Up Studies
MH  - *Hypoxia/complications
MH  - Placenta
MH  - Endothelin-1
OTO - NOTNLM
OT  - adult male offspring
OT  - cardiac ischemia-reperfusion injury
OT  - nMitoQ
OT  - placenta-targeted treatment
OT  - prenatal hypoxia
EDAT- 2023/05/26 19:14
MHDA- 2023/06/23 06:42
CRDT- 2023/05/26 13:02
PHST- 2023/06/23 06:42 [medline]
PHST- 2023/05/26 19:14 [pubmed]
PHST- 2023/05/26 13:02 [entrez]
AID - 10.1152/ajpheart.00238.2023 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2023 Jul 1;325(1):H136-H141. doi: 
      10.1152/ajpheart.00238.2023. Epub 2023 May 26.