Prenatal programming: adverse cardiac programming by gestational testosterone excess.

Arpita K Vyas,Ebony Gilbreath,Kristy A Mietelka,Vanessa Hoang,Vasantha Padmanabhan

doi:10.1038/srep28335

Abstract

Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.

Highlights

Effects in humans[17], any adverse cardiac programming in prenatally T-treated sheep may be the indirect consequence of IUGR and the insulin resistance induced by prenatal T excess[16,18]
A number of molecular mediators involved in insulin signaling such as phosphatidyl inositol-3 kinase (PI3K)/ protein kinase B (AKT)/mammalian target of rapamycin complex 1 signaling pathway have been implicated in cardiac hypertrophy[23,24]
Considering that prenatal T induces functional hyperandrogenism and insulin resistance in sheep[4,18], alters insulin signaling in liver and muscle[26], and both T and insulin have the potential to alter cardiac function, we hypothesized that prenatal T excess disrupts insulin signaling and upregulates molecular markers of cardiac hypertrophy leading to adverse cardiac remodeling

Summary

Introduction

Effects in humans[17], any adverse cardiac programming in prenatally T-treated sheep may be the indirect consequence of IUGR and the insulin resistance induced by prenatal T excess[16,18]. A number of molecular mediators involved in insulin signaling such as phosphatidyl inositol-3 kinase (PI3K)/ protein kinase B (AKT)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway have been implicated in cardiac hypertrophy[23,24]. Considering that prenatal T induces functional hyperandrogenism and insulin resistance in sheep[4,18], alters insulin signaling in liver and muscle[26], and both T and insulin have the potential to alter cardiac function, we hypothesized that prenatal T excess disrupts insulin signaling and upregulates molecular markers of cardiac hypertrophy leading to adverse cardiac remodeling

Methods

Results

Conclusion