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Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression

a gene expression and gene technology, applied in the field of molecular biology, can solve the problems of sudden death, heart failure, dilated cardiomyopathy,

Inactive Publication Date: 2009-04-02
OLSON ERIC N +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods and compositions for preventing or reversing cardiac hypertrophy, which can lead to heart failure and sudden death. The invention is based on the discovery of specific enzymes (HDAC 4 and HDAC 5) that can inhibit the process of cardiac hypertrophy. The patent describes methods for identifying inhibitors of cardiac hypertrophy using in vitro deacetylation reactions and in vivo animal models. The invention also provides a method for treating cardiac hypertrophy in animals by providing HDAC 4 or 5 to cardiac tissue or by administering a traditional coronary heart disease drug formulation. The patent also describes a method for identifying individuals at risk of developing cardiac hypertrophy by assessing their HDAC 4 or 5 genotype.

Problems solved by technology

While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, sustained hypertrophy can lead to dilated cardiomyopathy, heart failure, and sudden death.

Method used

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  • Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression
  • Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression
  • Methods and compositions relating to HDAC 4 and 5 regulation of cardiac gene expression

Examples

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example 1

Materials and Methods

[0259]Preparation of primary rat cardiomyocytes. cardiomyocyte cultures are prepared by dissociation of 1-day old neonatal rat hearts and were differentially plated to remove fibroblasts. To induce the hypertrophic response, AngII and PE are added to cardiomyocyte cultures at 10 mM and 10 μM, respectively, in serum-free M199 media. The culture media containing either agonist is changed every 12 hours for a period of 72 hours.

[0260]Immunocytochemistry. To visualize sarcomeric organization in primary cardiomyocytes, anti-α-actinin mouse monoclonal antibody is used (Sigma). Cells are washed in 1×PBS, fixed in 3.7% paraformaldehyde for 5 minutes, washed three times with 1×PBS and then pre-blocked in 1×PBS containing 2% horse serum, 2% BSA, and 0.1% NP40 for 30 minutes. Anti-α-actinin antibody is added at a dilution of 1:800 in fresh pre-block solution and incubated for an additional 30 minutes. Subsequently, cells are washed three times in 1×PBS with 0.1% NP40. Anti...

example 2

[0263]The Role of MEF2 in Cardiac Gene Expression.

[0264]Structure-function studies. There are four vertebrate MEF2 genes, whose products are schematized in FIG. 1. Through extensive mutational analyses, the functional domains of the MEF2 proteins have been characterized (Molkentin et al., 1995; Martin et al., 1993; Molkentin et al., 1996a; 1996b). These studies demonstrate that the N-terminal MADS-box mediates DNA binding and dimerization. The adjacent MEF2 domain influences DNA binding affinity and interactions with myogenic bHLH proteins, and the C-terminal regions of the MEF2 factors contain multiple independent transcriptional activation domains.

[0265]Cooperative activation of muscle transcription by MEF2 and myogenic bHLH factors. In the skeletal muscle lineage, MEF2 acts combinatorially with members of the MyoD family of bHLH transcription factors to activate muscle gene transcription. It has been demonstrated that the MADS-box of the MEF2 proteins interacts directly with the ...

example 3

Induction of MEF7 Activity In Vitro by Hypertrophic Signaling

[0269]In light of the ability of MEF2 to respond to calcium-dependent signal transduction pathways in T cells, the inventors have investigated whether the same pathways also activate MEF2 in cardiomyocytes. As shown in FIG. 4, activated calcineurin or CaMKIV can upregulate a MEF2-dependent luciferase reporter gene in transfected cardiomyocytes and together these calcium-sensitive signaling enzymes synergistically activate MEF2-dependent gene expression. In DNA binding assays, an increase in MEF2 DNA binding activity in response to activated calcineurin and CaMKIV is not observed suggesting that the increase in MEF2 transcriptional activity reflects a post-translational mechanism. When the C-terminus of MEF2C, which contains the transcription activation domains (TADs), but lacks the MADS and MEF2 domains required for DNA binding and dimerization, is fused to the DNA binding domain of the yeast transcription factor GAL4, the...

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Abstract

The present invention relates to cardiac hypertrophy. More particularly, the present invention defines the molecular events linking calcium stimulation to cardiac hypertrophy. More specifically, the present invention shows that Ca2+ stimulation of the hypertrophic response is mediated through an HDAC 4 and 5 interaction with MEF2, and that phosphorylation of HDACs results in loss of HDAC-mediated repression of MEF2 hypertrophic action. Thus, the present invention provides methods and compositions of treating cardiac hypertrophy, as well as methods and compositions for identifying subjects at risk for cardiac hypertrophy. Further provided are methods for the detection of compounds having therapeutic activity toward cardiac hypertrophy.

Description

[0001]The present application claims priority to U.S. Provisional Application 60 / 150,048, filed on Aug. 20, 1999.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates generally to the field of molecular biology. More particularly, it concerns the discovery of a central mediator of cardiac hypertrophy.[0004]2. Description of Related Art[0005]Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac disease, including those arising from hypertension, mechanical load, myocardial infarction, cardiac arrythmias, endocrine disorders and genetic mutations in cardiac contractile protein genes. While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, sustained hypertrophy can lead to dilated cardiomyopathy, heart failure, and sudden death. In the United States, approximately half a million individuals are diagnosed with heart failure each year, with a mortality rate approaching...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K38/46C12Q1/68A61P9/10A01K67/027A61K35/76A61K38/43A61K45/00A61P9/00C12N15/09C12Q1/44C12Q1/48C12Q1/54C12Q1/66G01N33/15G01N33/50G01N33/68
CPCC12Q1/44G01N33/6887G01N2800/32G01N2333/916G01N2500/00G01N2333/4712A61P9/00A61P9/10
Inventor OLSON, ERIC N.LU, JIANRONGMCKINSEY, TIMOTHY
Owner OLSON ERIC N
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