PMID- 34042301
OWN - NLM
STAT- MEDLINE
DCOM- 20220120
LR  - 20220120
IS  - 2051-817X (Electronic)
IS  - 2051-817X (Linking)
VI  - 9
IP  - 10
DP  - 2021 May
TI  - Early life stress induces dysregulation of the heme pathway in adult mice.
PG  - e14844
LID - 10.14814/phy2.14844 [doi]
LID - e14844
AB  - Early life stress (ELS) is associated with cardiovascular disease (CVD) risk in 
      adulthood, but the underlying vascular mechanisms are poorly understood. 
      Increased hemoglobin and heme have recently been implicated to mediate 
      endothelial dysfunction in several vascular diseases. Chronic physiological 
      stress is associated with alterations in the heme pathway that have been 
      well-described in the literature. However, very little is known about the heme 
      pathway with exposure to ELS or chronic psychosocial stress. Utilizing a mouse 
      model of ELS, maternal separation with early weaning (MSEW), we previously 
      reported that MSEW induces endothelial dysfunction via increased superoxide 
      production. We reasoned that heme dysregulation may be one of the culprits 
      induced by MSEW and sustained throughout adulthood; thus, we hypothesized that 
      MSEW induces heme dysfunction. We investigated whether circulating levels of 
      heme, a circulating pro-oxidant mediator, are increased by MSEW and examined the 
      role of the heme metabolic pathway and heme homeostasis in this process. We found 
      that circulating levels of heme are increased in mice exposed to MSEW and that 
      plasma from MSEW mice stimulated higher superoxide production in cultured mouse 
      aortic endothelial cells (MAECs) compared to plasma from normally reared mice. 
      The heme scavenger hemopexin blunted this enhanced superoxide production. Splenic 
      haptoglobin abundance was significantly lower and hemoglobin levels per red blood 
      cell were significantly higher in MSEW versus control mice. These findings lead 
      us to propose that ELS induces increased circulating heme through dysregulation 
      of the haptoglobin-hemoglobin system representing a mechanistic link between ELS 
      and CVD risk in adulthood.
CI  - (c) 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on 
      behalf of The Physiological Society and the American Physiological Society.
FAU - Pettway, Yasminye D
AU  - Pettway YD
AUID- ORCID: 0000-0001-6660-3013
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Neder, Thomas H
AU  - Neder TH
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Ho, Dao H
AU  - Ho DH
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Fox, Brandon M
AU  - Fox BM
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Burch, Mariah
AU  - Burch M
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Colson, Jackson
AU  - Colson J
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Liu, Xiaofen
AU  - Liu X
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Kellum, Cailin E
AU  - Kellum CE
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Hyndman, Kelly A
AU  - Hyndman KA
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FAU - Pollock, Jennifer S
AU  - Pollock JS
AUID- ORCID: 0000-0003-1956-0449
AD  - Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of 
      Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
LA  - eng
GR  - P01 HL067669/HL/NHLBI NIH HHS/United States
GR  - R25 DK112731/DK/NIDDK NIH HHS/United States
GR  - K01 DK105038/DK/NIDDK NIH HHS/United States
GR  - R03 DK120503/DK/NIDDK NIH HHS/United States
GR  - R25 GM086256/GM/NIGMS NIH HHS/United States
GR  - F30 DK107194/DK/NIDDK NIH HHS/United States
GR  - T32 DK116672/DK/NIDDK NIH HHS/United States
GR  - P01 HL136267/HL/NHLBI NIH HHS/United States
GR  - U01 HL117684/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Physiol Rep
JT  - Physiological reports
JID - 101607800
RN  - 42VZT0U6YR (Heme)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Animals, Newborn
MH  - Endothelium, Vascular/metabolism
MH  - Female
MH  - Heme/*metabolism
MH  - Male
MH  - *Maternal Deprivation
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pregnancy
MH  - Signal Transduction/*physiology
MH  - Stress, Psychological/*blood/*psychology
MH  - *Weaning
PMC - PMC8157772
OTO - NOTNLM
OT  - early life stress
OT  - haptoglobin
OT  - heme
OT  - hemoglobin
OT  - maternal separation with early weaning
OT  - superoxide
EDAT- 2021/05/28 06:00
MHDA- 2022/01/21 06:00
PMCR- 2021/05/27
CRDT- 2021/05/27 09:03
PHST- 2021/03/25 00:00 [revised]
PHST- 2021/02/21 00:00 [received]
PHST- 2021/04/01 00:00 [accepted]
PHST- 2021/05/27 09:03 [entrez]
PHST- 2021/05/28 06:00 [pubmed]
PHST- 2022/01/21 06:00 [medline]
PHST- 2021/05/27 00:00 [pmc-release]
AID - PHY214844 [pii]
AID - 10.14814/phy2.14844 [doi]
PST - ppublish
SO  - Physiol Rep. 2021 May;9(10):e14844. doi: 10.14814/phy2.14844.