Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function

Joseph A Hill; Beverly Rothermel; Ki-Dong Yoo; Barry Cabuay; Elaine Demetroulis; Robert M Weiss; William Kutschke; Rhonda Bassel-Duby; R Sanders Williams

doi:10.1074/jbc.M110722200

Back

Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function

Journal article

Open access

Peer reviewed

Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function

Joseph A Hill, Beverly Rothermel, Ki-Dong Yoo, Barry Cabuay, Elaine Demetroulis, Robert M Weiss, William Kutschke, Rhonda Bassel-Duby and R Sanders Williams

The Journal of biological chemistry, Vol.277(12), pp.10251-10255

03/22/2002

DOI: 10.1074/jbc.M110722200

PMID: 11786544

Files and links (1)

url

https://doi.org/10.1074/jbc.M110722200View

Published (Version of record) Open Access

Abstract

Calcineurin is a Ca(2+)/calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.

Blood Pressure

Up-Regulation

Echocardiography

Heart Diseases - metabolism

Humans

Male

Mice, Transgenic

Myocardium - pathology

Electroencephalography

RNA, Messenger - metabolism

Hypertrophy - metabolism

Pressure

Aorta - pathology

Dose-Response Relationship, Drug

Calcineurin Inhibitors

Blotting, Northern

Animals

Time Factors

Protein Isoforms

Protein Binding

Mice

DNA, Complementary - metabolism

Calcineurin - metabolism

RNA - metabolism

Details

Title: Subtitle: Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function
Creators: Joseph A Hill - Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081, USA. joseph-hill@uiowa.edu
Beverly Rothermel
Ki-Dong Yoo
Barry Cabuay
Elaine Demetroulis
Robert M Weiss
William Kutschke
Rhonda Bassel-Duby
R Sanders Williams
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.277(12), pp.10251-10255
DOI: 10.1074/jbc.M110722200
PMID: 11786544
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: HL03908 / NHLBI NIH HHS
Language: English
Date published: 03/22/2002
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094646802771

Metrics

30 Record Views

100 Times Cited - Web of Science