Early Postnatal Cardiac Development in Atrial Natriuretic Peptide Gene-Disrupted Mice

Abstract

The natriuretic peptide system (NPS) is a hormonal system critical to mammalian cardiovascular homeostasis. The purpose of the present study was to investigate the role of ANP during early postnatal cardiac development by i) monitoring the development of cardiac hypertrophy during early postnatal development of the ANP-/- mice, and ii) comparing morphologic, morphometric and molecular differences in ANP+/+ mice compared to ANP-/- mice during this developmental period. Age matched male ANP+/+ and ANP-/- mice, aged day 1 and weeks 1 to 5, were evaluated. Body weight, organ weights and hematocrit were recorded. RNA was isolated and quantitative real-time RT-PCR was used to monitor cardiac gene expression. An additional cohort of animals was used for morphologic and morphometric analysis. Heart weight to body weight ratio (HW/BW) was dramatically higher in ANP-/- animals at all time points, indicating cardiac hypertrophy is established before the advent of adult blood pressure. Molecular analysis of gene expression revealed a compensatory response of the NPS in the ANP-/- mice. Specifically an up-regulation of BNP expression in ANP-/- mice was noted throughout postnatal development. Similarly, NPR-A and NPR-C demonstrated compensatory action for the lack of ANP, as expressional levels also varied throughout development. Morphological analysis of cardiac vasculature revealed striking structural differences between ANP+/+ and ANP-/- mice. Quantitative stereological analysis of LM images indicated a greater vessel volume in ANP-/- compared to ANP+/+ mice. This study demonstrates that alterations in early molecular events, such as changes in NPS expression, may be responsible for the maintenance and progression of cardiac hypertrophy during early postnatal development in the ANP-/- mice. The absence of ANP during this critical period of development has a profound impact on final cardiac structure leading to future pathological states.