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

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 Ca 2+ 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.

1 - 19 . (canceled) 
     
     
         20 . A method for treating cardiac hypertrophy in an animal comprising providing at least one of HDAC 4 or 5 to cardiac tissue in said animal. 
     
     
         21 . The method of  claim 20 , wherein both HDAC 4 and 5 are provided. 
     
     
         22 . The method of  claim 20 , wherein said at least one of HDAC 4 or 5 is provided by transferring an expression cassette encoding HDAC 4 or HDAC 5, under the control of a promoter active in cardiac, into said cardiac tissue. 
     
     
         23 . The method of  claim 20 , wherein said expression cassette is a viral expression vector and transferring is achieved by infection of said cardiac tissue with a viral particle containing said viral expression vector. 
     
     
         24 . The method of  claim 23 , wherein said viral expression vector is derived from adenovirus, retrovirus, adeno-associated virus, herpesvirus and vaccinia virus. 
     
     
         25 . The method of  claim 20 , further comprising the step of administering a traditional coronary heart disease drug formulation to said animal. 
     
     
         26 . A method for treating cardiac hypertrophy in an animal comprising providing an HDAC 4 or 5 agonist to said animal. 
     
     
         27 . The method of  claim 26 , wherein said agonist increases HDAC 4 or 5 synthesis. 
     
     
         28 . The method of  claim 26 , wherein said agonist increases HDAC 4 or 5 stability. 
     
     
         29 . The method of  claim 26 , wherein said agonist increase HDAC 4 or 5 activity. 
     
     
         30 . The method of  claim 26 , further comprising the step of administering a traditional coronary heart disease drug formulation to said animal. 
     
     
         31 . A method for identifying a subject at risk of developing cardiac hypertrophy comprising:
 (a) obtaining a biological sample from said subject; and   (b) assessing an HDAC 4 or 5 genotype in cells of said sample.   
     
     
         32 . The method of  claim 31 , wherein said assessing comprises determining an HDAC 4 or 5 polynucleotide sequence. 
     
     
         33 . The method of  claim 32 , wherein said polynucleotide sequence is a coding sequence. 
     
     
         34 . The method of  claim 31 , wherein said assessing comprises determining an HDAC 4 or 5 RFLP pattern. 
     
     
         35 . The method of  claim 31 , wherein said assessing comprises determining the size of an HDAC 4 or 5 transcript or gene. 
     
     
         36 . The method of  claim 31 , wherein said assessing further comprises amplifying an HDAC 4 or 5 transcript or gene. 
     
     
         37 . The method of  claim 31 , wherein the biological sample is cardiac tissue 
     
     
         38 - 67 . (canceled) 
     
     
         68 . A method for treating cardiac hypertrophy in an animal comprising providing an inhibitor of HDAC phosphorylation to an animal. 
     
     
         69 . The method of  claim 68 , wherein said animal is a human. 
     
     
         70 . The method of  claim 68 , wherein said inhibitor is an inhibitor of Cam kinase. 
     
     
         71 . The method of  claim 70 , wherein said inhibitor of Cam kinase is KN62. 
     
     
         72 . The method of  claim 68 , further comprising providing a second pharmaceutical composition to said animal. 
     
     
         73 . The method of claim  62 , wherein said second pharmaceutical is selected from the group consisting of “beta blockers”, anti-hypertensives, cardiotonics, anti-thrombotics, vasodilators, hormone antagonists, endothelin antagonists, cytokine inhibitors/blockers, calcium channel blockers, phosphodiesterase inhibitors and angiotensin type 2 antagonists. 
     
     
         74 . The method of  claim 68 , wherein the HDAC is HDAC 4. 
     
     
         75 . The method of  claim 68 , wherein the HDAC is HDAC 5. 
     
     
         76 . The method of  claim 26 , further comprising providing a second pharmaceutical to said animal. 
     
     
         77 . The method of  claim 26 , wherein the HDAC 4 is provided. 
     
     
         78 . The method of  claim 26 , wherein the HDAC 5 is provided. 
     
     
         79 . The method of  claim 26 , wherein the animal is a human. 
     
     
         80 - 83 . (canceled)