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

A method for preparing a candidate inhibitor of cardiac hypertrophy comprising:

• (a) providing an enzyme preparation comprising HDAC 4 or HDAC 5 enzyme, or a cell expressing HDAC 4 or HDAC 5 enzyme;
• (b) contacting the enzyme preparation or cell with a test substance;
• (c) determining in vitro MEF-2 binding activity of HDAC 4 or HDAC 5 in the enzyme preparation, MEF-2 binding activity of HDAC 4 or HDAC 5 in the cell, expression of HDAC 4 or HDAC 5 in the cell, or nuclear localization of HDAC 4 or HDAC 5 in the cell;
• (d) comparing the activity of the enzyme preparation, or the activity, expression or nuclear localization of HDAC 4 or HDAC 5 in the cell in step (c) with the activity of the enzyme preparation, or the activity, expression or nuclear localization of HDAC 4 or HDAC 5 in the cell in the absence of said test substance, wherein increased activity, increased activity, expression or increased nuclear localization in the presence of said test substance, as compared to activity, activity, expression or nuclear localization in the absence of said test substance, identifies said test substance as a candidate inhibitor of cardiac hypertrophy;
• and then
• (e) preparing the candidate inhibitor.

A method for identifying a candidate inhibitor of cardiac hypertrophy comprising:

• (a) providing a cell expressing an HDAC 4 or HDAC 5 enzyme;
• (b) contacting the cell with a test substance;
• (c) determining a phenotype of the cell in step (b), the phenotype comprising:
• (i) HDAC 4 or HDAC 5 expression level, or
• (ii) HDAC 4 or HDAC 5 nuclear localization;
• and
• (d) comparing the phenotype determined in step (c) with the same phenotype of the cell in the absence of the test substance,
• wherein increased expression or nuclear localization in the presence of the test substance, as compared to expression or nuclear localization in the absence of the test substance, identifies the test substance as a candidate inhibitor of cardiac hypertrophy.