Inhibition of histone deacetylase as a treatment for cardiac hypertrophy

Abstract

The present invention provides for methods of treating and preventing cardiac hypertrophy. Class II HDACs, which are known to participate in regulation of chromatin structure and gene expression, have been shown to have beneficial effects on cardiac hypertrophy. Surprisingly, the present invention demonstrates that HDAC inhibitors inhibit cardiac hypertrophy by inhibiting fetal cardiac gene expression and interfering with sarcomeric organization.

1 . A method of treating hypertension comprising: 
 (a) identifying a patient having hypertension; and    (b) administering to said patient a histone deacetylase inhibitor.    
     
     
         2 . The method of  claim 1 , wherein said histone deacetylase inhibitor is selected from the group consisting of trichostatin A, trapoxin B, MS 275-27, m-carboxycinnamic acid bis-hydroxamide, depudecin, oxamflatin, apicidin, suberoylanilide hydroxamic acid, Scriptaid, pyroxamide, 2-amino-8-oxo-9,10-epoxy-decanoyl, 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide and FR901228.  
     
     
         3 . The method of  claim 1 , wherein administering comprises intravenous administration of said histone deacetylase inhibitor.  
     
     
         4 . The method of  claim 1 , wherein administering comprises oral, transdermal, sustained release, suppository, or sublingual administration.  
     
     
         5 . The method of  claim 1 , further comprising administering to said patient a second therapeutic regimen.  
     
     
         6 . The method of  claim 5  wherein said second therapeutic regimen is selected from the group consisting of a beta blocker, an iontrope, diuretic, ACE-I, AII antagonist, and Ca++-blocker.  
     
     
         7 . The method of  claim 5 , wherein said second therapeutic regimen is administered at the same time as said histone deacetylase inhibitor.  
     
     
         8 . The method of  claim 5 , wherein said second therapeutic regimen is administered either before or after said histone deacetylase inhibitor.  
     
     
         9 . The method of  claim 1 , wherein treating comprises improving one or more symptoms of hypertension.  
     
     
         10 . The method of  claim 9 , wherein improving said one or more symptoms comprises increased exercise capacity, increased blood ejection volume, decreased left ventricular end diastolic pressure, decreased pulmonary capillary wedge pressure, increased cardiac output, improved cardiac index, decreased pulmonary artery pressures, decreased left ventricular end systolic and diastolic dimensions, decreased left and right ventricular wall stress, or wall tension, or improved quality of life, disease-related morbidity and mortality.  
     
     
         11 . A method of preventing hypertension comprising: 
 (a) identifying a patient at risk of developing hypertension; and    (b) administering to said patient a histone deacetylase inhibitor.    
     
     
         12 . The method of  claim 11 , wherein said histone deacetylase inhibitor is selected from the group consisting of trichostatin A, trapoxin B, MS 275-27, m-carboxycinnamic acid bis-hydroxamide, depudecin, oxamflatin, apicidin, suberoylanilide hydroxamic acid, Scriptaid, pyroxamide, 2-amino-8-oxo-9, 10-epoxy-decanoyl, 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide and FR901228.  
     
     
         13 . The method of  claim 11 , wherein administering comprises intravenous administration of said histone deacetylase inhibitor.  
     
     
         14 . The method of  claim 11 , wherein administering comprises oral, transdermal, sustained release, suppository, or sublingual administration.  
     
     
         15 . The method of  claim 11 , wherein the patient at risk may exhibit one or more of uncorrected valvular disease, chronic angina and/or recent myocardial infarction.  
     
     
         16 - 50 . (canceled)  
     
     
         51 . The method of  claim 1 , wherein hypertension is long-standing uncontrolled hypertension.  
     
     
         52 . The method of  claim 11 , wherein hypertension is long-standing uncontrolled hypertension.