Gestational stress causes heart defects by inducing the unfolded protein response

H Shi, V O'Reilly, J Moreau, R Stocker, R Graham, G Chapman, D Sparrow and S Dunwoodie

Victor Chang Cardiac Research Institute

Congenital heart disease (CHD) is the most common human birth defect and yet 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 outflow tract types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which rapidly decreases FGFR1 protein expression and inhibits FGF signaling in cardiac progenitor cells of the second heart field. 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.