Linked Life Data

20600098

Source:http://linkedlifedata.com/resource/pubmed/id/20600098

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-8-31
pubmed:abstractText
To identify new mediators of cardiac hypertrophy, we performed a genome-wide mRNA screen of stretched neonatal rat cardiomyocytes (NRCMs). In addition to known members of the hypertrophic gene program, we found the novel sarcomeric Z-disc LIM protein Lmcd1/Dyxin markedly upregulated. Consistently, Lmcd1 was also induced in several mouse models of myocardial hypertrophy suggesting a causal role in cardiac hypertrophy. We overexpressed Lmcd1 in NRCM, which led to cardiomyocyte hypertrophy and induction of the hypertrophic gene program. Likewise, the calcineurin-responsive gene RCAN1-4 was found significantly upregulated. Conversely, knockdown of Lmcd1 blunted the response to hypertrophic stimuli such as stretch and phenylephrine (PE), suggesting that Lmcd1 is required for the hypertrophic response. Furthermore, PE-mediated activation of calcineurin was completely blocked by knockdown of Lmcd1. To confirm these results in vivo, we generated transgenic mice with cardiac-restricted overexpression of Lmcd1. Despite normal cardiac function, adult transgenic mice displayed significant cardiac hypertrophy, again accompanied by induction of hypertrophic marker genes such as ANF and alpha-skeletal actin. Likewise, Rcan1-4 was found upregulated. Moreover, when crossed with transgenic mice overexpressing constitutionally active calcineurin, Lmcd1 transgenic mice revealed an exacerbated cardiomyopathic phenotype with depressed contractile function and further increased cardiomyocyte hypertrophy. We show that the novel z-disc protein Lmcd1/Dyxin is significantly upregulated in several models of cardiac hypertrophy. Lmcd1/Dyxin potently induces cardiomyocyte hypertrophy both in vitro and in vivo, while knockdown of this molecule prevents hypertrophy. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway. Lmcd1/Dyxin may thus represent an attractive target for novel antihypertrophic strategies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1095-8584
pubmed:author
pubmed:copyrightInfo
Copyright 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
673-82
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Lmcd1/Dyxin, a novel Z-disc associated LIM protein, mediates cardiac hypertrophy in vitro and in vivo.
pubmed:affiliation
Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't