Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

Katja Grabowski,Jaap A Joles,Reinhold Kreutz,Mona Riemenschneider,Leonard Schulte,Angela Schulz,Monika Stoll,Anika Witten

doi:10.1371/journal.pone.0116807

Katja Grabowski, Jaap A Joles + Show 6 more

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https://doi.org/10.1371/journal.pone.0116807

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Abstract

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

Highlights

Left ventricular (LV) hypertrophy (LVH) is a major sign of cardiac adaption to high blood pressure and the most common cause of cardiac hypertrophy [1]
Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension
Further bioinformatic analysis presented EF-hand calcium binding domain 6 (Efcab6) as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%)

Summary

Introduction

Left ventricular (LV) hypertrophy (LVH) is a major sign of cardiac adaption to high blood pressure and the most common cause of cardiac hypertrophy [1]. Due to the high prevalence of arterial hypertension, LVH will soon become the most common risk factor for cardiac failure worldwide [2]. Independent of blood pressure, LVH alone profoundly affects morbidity and mortality from cardiovascular diseases [3,4,5]. It is still poorly understood why only one part of hypertensive patients develop LVH over time. And population studies demonstrated that LV mass variation is clearly influenced by genetic factors [6,7]. This is supported by genetic analysis of inbred rat models, including hypertensive rat strains [8,9]

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