Influence of Natriuretic Peptide Receptor-1 on Survival and Cardiac Hypertrophy during Development

Nicola J.A. Scott (1) , Leigh. J. Ellmers (1) , John G. Lainchbury (2) , Nobuyo Maeda (3) , Oliver Smithies (3) , A. Mark Richards (1) , Vicky A. Cameron (1)

1 Department of Medicine
2 Department of Cardiology
3 Department of Pathology and Laboratory Medicine

The heart adapts to an increased workload through the activation of a hypertrophic response within the cardiac ventricles. This response is characterized by both an increase in the size of the individual cardiomyocytes and an induction of a panel of genes normally expressed in the embryonic and neonatal ventricle, such as atrial natriuretic peptide (ANP). ANP and brain natriuretic peptide (BNP) exert their biological actions through activation of the natriuretic peptide receptor-1 (). The current study examined mice lacking () activity and investigated the effects of the absence of signaling during cardiac development on embryo viability, cardiac structure and gene and protein expression. embryos were collected at embryonic day (ED) 12.5, 15.5 and neonatal day 1 (ND 1). embryos occurred at the expected Mendelian frequency at ED 12.5, but knockout numbers were significantly decreased at ED 15.5 and ND 1. There was no indication of cardiac structural abnormalities in surviving embryos. However, embryos exhibited cardiac enlargement (without fibrosis) from ED 15.5 as well as significantly increased ANP mRNA and protein expression compared to wild-type (WT) mice, but no concomitant increase in expression of the hypertrophy-related transcription factors, Mef2A, Mef2C, GATA-4, GATA-6 or serum response factor (SRF). However, there was a significant decrease in Connexin-43 (Cx43) gene and protein expression at mid-gestation in embryos. Our findings suggest that the mechanism by which natriuretic peptide signaling influences cardiac development in mice is distinct from that seen during the development of pathological cardiac hypertrophy and fibrosis. The decreased viability of embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility.

Mots clés: Akt1; atrial natriuretic peptide; calcineurin A; cardiac hypertrophy; Connexin 43; gene expression; heart development; Npr1; transcription factors

Nicola J.A. Scott, Leigh. J. Ellmers, John G. Lainchbury, Nobuyo Maeda, Oliver Smithies, et al.. Influence of Natriuretic Peptide Receptor-1 on Survival and Cardiac Hypertrophy during Development. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2009, 1792 (12), pp.1175. ⟨10.1016/j.bbadis.2009.09.009⟩. ⟨hal-00562938⟩