Placental treatment improves cardiac tolerance to ischemia/reperfusion insult in adult male and female offspring exposed to prenatal hypoxia

Nataliia Hula; Floor Spaans; Jennie Vu; Anita Quon; Raven Kirschenman; Christy-Lynn M Cooke; Tom J Phillips; C Patrick Case; Sandra T Davidge

doi:10.1016/j.phrs.2021.105461

Placental treatment improves cardiac tolerance to ischemia/reperfusion insult in adult male and female offspring exposed to prenatal hypoxia

Pharmacol Res. 2021 Mar:165:105461. doi: 10.1016/j.phrs.2021.105461. Epub 2021 Jan 26.

Authors

Nataliia Hula¹, Floor Spaans², Jennie Vu³, Anita Quon⁴, Raven Kirschenman⁵, Christy-Lynn M Cooke⁶, Tom J Phillips⁷, C Patrick Case⁸, Sandra T Davidge⁹

Affiliations

¹ Department of Physiology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: hula@ualberta.ca.
² Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: floortje@ualberta.ca.
³ Department of Physiology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: jvu@ualberta.ca.
⁴ Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: aquon@ualberta.ca.
⁵ Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: raven@ualberta.ca.
⁶ Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: christyl@ualberta.ca.
⁷ Dementia Research Institute, Cardiff University, Cardiff, CF10 3AT, UK. Electronic address: PhillipsT10@cardiff.ac.uk.
⁸ Musculoskeletal Research Unit, University of Bristol, Bristol, BS10 5NB, UK. Electronic address: pacpc@my.bristol.ac.uk.
⁹ Department of Physiology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Department of Obstetrics and Gynecology, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, T6G 2S2, Alberta, Canada. Electronic address: sandra.davidge@ualberta.ca.

PMID: 33513355
DOI: 10.1016/j.phrs.2021.105461

Abstract

Offspring born from complicated pregnancies are at greater risk of cardiovascular disease in adulthood. Prenatal hypoxia is a common pregnancy complication that results in placental oxidative stress and impairs fetal development. Adult offspring exposed to hypoxia during fetal life are more susceptible to develop cardiac dysfunction, and show decreased cardiac tolerance to an ischemia/reperfusion (I/R) insult. To improve offspring cardiac outcomes, we have assessed the use of a placenta-targeted intervention during hypoxic pregnancies, by encapsulating the mitochondrial antioxidant MitoQ into nanoparticles (nMitoQ). We hypothesized that maternal nMitoQ treatment during hypoxic pregnancies improves cardiac tolerance to I/R insult in adult male and female offspring. Pregnant Sprague-Dawley rats were exposed to normoxia (21 % O²) or hypoxia (11 % O²) from gestational day 15-20, after injection with 100 μL saline or nMitoQ (125 μM) on GD15 (n=6-8/group). Male and female offspring were aged to 4 months. Both male and female offspring from hypoxic pregnancies showed reduced cardiac tolerance to I/R (assessed ex vivo using the isolated working heart technique) which was ameliorated by nMitoQ treatment. To identify potential molecular mechanisms for the changes in cardiac tolerance to I/R, cardiac levels/phosphorylation of proteins important for intracellular Ca²⁺ cycling were assessed with Western blotting. In prenatally hypoxic male offspring, improved cardiac recovery from I/R by nMitoQ was accompanied by increased cardiac phospholamban and phosphatase 2Ce levels, and a trend to decreased Ca²⁺/calmodulin-dependent protein kinase IIδ phosphorylation. In contrast, in female offspring, nMitoQ treatment in hypoxic pregnancies increased phospholamban and protein kinase Cε phosphorylation. Maternal nMitoQ treatment improves cardiac tolerance to I/R insult in adult offspring and thus has the potential to improve the later-life trajectory of cardiovascular health of adult offspring born from pregnancies complicated by prenatal hypoxia.

Keywords: Cardiovascular dysfunction; Developmental origins of health and disease; Ischemia/reperfusion injury; MitoQ; Placenta-targeted treatment; Prenatal hypoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Animals
Antioxidants / administration & dosage
Cardiovascular Diseases / metabolism*
Cardiovascular Diseases / prevention & control
Female
Hypoxia / drug therapy
Hypoxia / metabolism*
Male
Nanoparticles / administration & dosage
Organophosphorus Compounds / administration & dosage*
Placenta / drug effects
Placenta / metabolism*
Pregnancy
Prenatal Exposure Delayed Effects / drug therapy
Prenatal Exposure Delayed Effects / metabolism*
Rats
Rats, Sprague-Dawley
Reperfusion Injury / drug therapy
Reperfusion Injury / metabolism*
Ubiquinone / administration & dosage
Ubiquinone / analogs & derivatives*

Substances

Antioxidants
Organophosphorus Compounds
Ubiquinone
mitoquinone

Grants and funding

FS154313/CIHR/Canada