Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking ELTD1

Hong Jiang,Dingsheng Jiang,Yan Zhang,Jinfeng Xiao,Guangpu Fan,Rui Zhang,Hongliang Li

doi:10.1371/journal.pone.0035779

Abstract

BackgroundEpidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is developmentally upregulated in the heart. Little is known about the relationship between ELTD1 and cardiac diseases. Therefore, we aimed to clarify the role of ELTD1 in pressure overload–induced cardiac hypertrophy.Methods and ResultsC57BL/6J wild-type (WT) mice and ELTD1-knockout (KO) mice were subjected to left ventricular pressure overload by descending aortic banding (AB). KO mice exhibited more unfavorable cardiac remodeling than WT mice 28 days post AB; this remodeling was characterized by aggravated cardiomyocyte hypertrophy, thickening of the ventricular walls, dilated chambers, increased fibrosis, and blunted systolic and diastolic cardiac function. Analysis of signaling pathways revealed enhanced extracellular signal-regulated kinase (ERK) and the c-Jun amino-terminal kinase (JNK) phosphorylation in response to ELTD1 deletion.ConclusionsELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by AB-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis. These effects are suggested to originate from the activation of the ERK and JNK pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease.

Highlights

Cardiac hypertrophy, an increase in heart mass, reflects a remodeling process in various cardiac diseases [1]
ELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by aortic banding (AB)-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis
These effects are suggested to originate from the activation of the extracellular signal-regulated kinase (ERK) and Jun amino-terminal kinase (JNK) pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease

Summary

Introduction

An increase in heart mass, reflects a remodeling process in various cardiac diseases [1]. The up-regulation of ELTD1 expression in rat and human hearts couples with the switch of myocardium from hyperplastic to hypertrophic growth [4] ,suggesting ELTD1 to be an important effector in this process. The extracellular domain of rat ELTD1 possesses several common protein kinase phosphorylation sites, and the short cytoplasmic tail carries a tyrosine kinase phosphorylation site that could couple to a tyrosine kinase signaling pathway [4]. The aims of this study were to determine if deletion of the ELTD1 gene affects pressure overload-induced cardiac hypertrophy and to identify the processes that underlie ELTD1-related differences in the hypertrophic growth response. We aimed to clarify the role of ELTD1 in pressure overload–induced cardiac hypertrophy

Objectives

Methods

Results

Conclusion