Gestational stress induces the unfolded protein response, resulting in heart defects

Hongjun Shi; Victoria C O'Reilly; Julie L M Moreau; Therese R Bewes; Michelle X Yam; Bogdan E Chapman; Stuart M Grieve; Roland Stocker; Robert M Graham; Gavin Chapman; Duncan B Sparrow; Sally L Dunwoodie

doi:10.1242/dev.136820

Gestational stress induces the unfolded protein response, resulting in heart defects

Development. 2016 Jul 15;143(14):2561-72. doi: 10.1242/dev.136820.

Affiliations

¹ The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
² The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
³ School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
⁴ School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia Sydney Translational Imaging Laboratory, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia Department of Radiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
⁵ The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
⁶ The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
⁷ The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia s.dunwoodie@victorchang.edu.au duncan.sparrow@dpag.ox.ac.uk.
⁸ The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia s.dunwoodie@victorchang.edu.au duncan.sparrow@dpag.ox.ac.uk.

PMID: 27436040
DOI: 10.1242/dev.136820

Abstract

Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

Keywords: FGF signaling; Heart development; Hypoxia; Unfolded protein response.

Publication types

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

MeSH terms

Animals
Apoptosis / drug effects
Cell Differentiation / drug effects
Cell Hypoxia / drug effects
Cell Proliferation / drug effects
Embryo, Mammalian / drug effects
Embryo, Mammalian / pathology
Female
Fibroblast Growth Factors / metabolism
Heart Defects, Congenital / etiology*
Heart Defects, Congenital / pathology*
Mice, Inbred C57BL
Oxygen / pharmacology
Phenotype
Pregnancy
Protein Biosynthesis / drug effects
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Signal Transduction / drug effects
Stress, Physiological* / drug effects
Unfolded Protein Response* / drug effects

Substances

Fibroblast Growth Factors
Receptor, Fibroblast Growth Factor, Type 1
Oxygen