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Cardiovasc Res. 2015 May 1;106(2):261-71. doi: 10.1093/cvr/cvv108. Epub 2015 Mar 13.

Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy.

Author information

1
Department of Medicine, Cardiovascular Division, Vanderbilt University School of Medicine, 2220 Pierce Ave, Preston Research Building, Rm 332, Nashville, TN 37232, USA.
2
Department of Medicine, Cardiovascular Division, Vanderbilt University School of Medicine, 2220 Pierce Ave, Preston Research Building, Rm 332, Nashville, TN 37232, USA Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
4
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Research Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232, USA.
5
Department of Medicine, Cardiovascular Division, Vanderbilt University School of Medicine, 2220 Pierce Ave, Preston Research Building, Rm 332, Nashville, TN 37232, USA Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA chee.lim@vanderbilt.edu.

Abstract

AIMS:

Accumulating evidence suggest that sarcomere signalling complexes play a pivotal role in cardiomyocyte hypertrophy by communicating stress signals to the nucleus to induce gene expression. Ankyrin repeat domain 1 (ANKRD1) is a transcriptional regulatory protein that also associates with sarcomeric titin; however, the exact role of ANKRD1 in the heart remains to be elucidated. We therefore aimed to examine the role of ANKRD1 in cardiomyocyte hypertrophic signalling.

METHODS AND RESULTS:

In neonatal rat ventricular myocytes, we found that ANKRD1 is part of a sarcomeric signalling complex that includes ERK1/2 and cardiac transcription factor GATA4. Treatment with hypertrophic agonist phenylephrine (PE) resulted in phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex. Knockdown of Ankrd1 attenuated PE-induced phosphorylation of ERK1/2 and GATA4, inhibited nuclear translocation of the ANKRD1 complex, and prevented cardiomyocyte growth. Mice lacking Ankrd1 are viable with normal cardiac function. Chronic PE infusion in wild-type mice induced significant cardiac hypertrophy with reactivation of the cardiac fetal gene program which was completely abrogated in Ankrd1 null mice. In contrast, ANKRD1 does not play a role in haemodynamic overload as Ankrd1 null mice subjected to transverse aortic constriction developed cardiac hypertrophy comparable to wild-type mice.

CONCLUSION:

Our study reveals a novel role for ANKRD1 as a selective regulator of PE-induced signalling whereby ANKRD1 recruits and localizes GATA4 and ERK1/2 in a sarcomeric macro-molecular complex to enhance GATA4 phosphorylation with subsequent nuclear translocation of the ANKRD1 complex to induce hypertrophic gene expression.

KEYWORDS:

CARP; GATA4; Hypertrophy; Sarcomere; Titin

PMID:
25770146
PMCID:
PMC4481572
DOI:
10.1093/cvr/cvv108
[Indexed for MEDLINE]
Free PMC Article

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