IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

Kimberley Wang, Darran N Tosh, Song Zhang, I Caroline McMillen, Jaime A Duffield, Doug A Brooks, Janna L Morrison

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.

Original languageEnglish
Pages (from-to)R627-R635
Number of pages9
JournalAmerican Journal of Physiology: Regulatory, Integrative and Comparative Physiology
Volume308
Issue number7
DOIs
Publication statusPublished - 1 Apr 2015
Externally publishedYes

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Somatomedin Receptors
Cardiomegaly
Low Birth Weight Infant
Birth Weight
Acetylation
Histones
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Insulin-Like Growth Factor II
Heterotrimeric GTP-Binding Proteins
Troponin I
Left Ventricular Hypertrophy
Cardiac Myocytes
Introns
Hypertrophy
Heart Ventricles
Proteins
Cardiovascular Diseases
Gene Expression
Weights and Measures
Messenger RNA

Cite this

Wang, Kimberley ; Tosh, Darran N ; Zhang, Song ; McMillen, I Caroline ; Duffield, Jaime A ; Brooks, Doug A ; Morrison, Janna L. / IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb. In: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. 2015 ; Vol. 308, No. 7. pp. R627-R635.
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IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb. / Wang, Kimberley; Tosh, Darran N; Zhang, Song; McMillen, I Caroline; Duffield, Jaime A; Brooks, Doug A; Morrison, Janna L.

In: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, Vol. 308, No. 7, 01.04.2015, p. R627-R635.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

AU - Wang, Kimberley

AU - Tosh, Darran N

AU - Zhang, Song

AU - McMillen, I Caroline

AU - Duffield, Jaime A

AU - Brooks, Doug A

AU - Morrison, Janna L

N1 - Copyright © 2015 the American Physiological Society.

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N2 - The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.

AB - The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life.

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KW - Age Factors

KW - Animals

KW - Animals, Newborn

KW - Birth Weight

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KW - GATA4 Transcription Factor

KW - GTP-Binding Protein alpha Subunits, Gq-G11

KW - Gene Expression Regulation

KW - Heart Ventricles

KW - Histone Deacetylases

KW - Histones

KW - Hypertrophy, Left Ventricular

KW - Myocardial Contraction

KW - Myocardium

KW - Phosphorylation

KW - Promoter Regions, Genetic

KW - RNA, Messenger

KW - Receptor, IGF Type 2

KW - Sheep

KW - Signal Transduction

KW - Troponin I

KW - Ventricular Function, Left

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1152/ajpregu.00346.2014

M3 - Article

VL - 308

SP - R627-R635

JO - American Journal of Physiology - Regulatory Intergrative Compartive Physiology

JF - American Journal of Physiology - Regulatory Intergrative Compartive Physiology

SN - 0363-6119

IS - 7

ER -