Intracellular inhibitors of Gq protein signaling

Abstract

The present invention relates, in general, to myocardial hypertrophy and, in particular, to agents that inhibit cardiac Gq-coupled receptor signaling and to methods of inhibiting myocardial hypertrophy using same.

What is claimed is:  
     
         1 . A method of treating or preventing myocardial hypertrophy in a mammal in need of such treatment or prevention comprising administering to said mammal an amount of an agent that inhibits Gq-mediated receptor signaling sufficient to effect said treatment or prevention.  
     
     
         2 . The method according to  claim 1  wherein said agent is a proteinaceous agent.  
     
     
         3 . The method according to  claim 2  wherein said agent is a carboxy terminal peptide of Gαq.  
     
     
         4 . The method according to  claim 1  wherein said agent is a non-proteinaceous agent.  
     
     
         5 . The method according to  claim 1  wherein said method is a method of treatment.  
     
     
         6 . The method according to  claim 1  wherein said method is a method of prevention.  
     
     
         7 . A method of treating or preventing vasculature smooth muscle cell migration or proliferation in a mammal in need of such treatment or prevention comprising administering to said mammal an amount of an agent that inhibits Gq-mediated receptor signaling sufficient to effect said treatment or prevention.  
     
     
         8 . The method according to  claim 7  wherein said agent is a proteinaceous agent.  
     
     
         9 . The method according to  claim 8  wherein said agent is a carboxy terminal peptide of Gαq.  
     
     
         10 . The method according to  claim 7  wherein said agent is a non-proteinaceous agent.  
     
     
         11 . The method according to  claim 7  wherein said method is a method of treatment.  
     
     
         12 . The method according to  claim 7  wherein said method is a method of prevention.  
     
     
         13 . A method of treating or preventing myocardial hypertrophy in a mammal in need of such treatment or prevention comprising administering to said mammal a construct comprising a promoter and a sequence encoding a peptide that inhibits Gq-mediated receptor signaling operably linked thereto, wherein said administration is effected under conditions such that said sequence is expressed, said peptide is produced and said treatment or prevention is thereby effected.  
     
     
         14 . The method according to  claim 13  wherein said promoter is a myocyte-specific promoter.  
     
     
         15 . The method according to  claim 13  wherein said construct is directly delivered to myocardial cells of said mammal.  
     
     
         16 . A method of treating or preventing vasculature smooth muscle cell migration or proliferation in a mammal in need of such treatment or prevention comprising administering to said mammal a construct comprising a promoter and a sequence encoding a peptide that inhibits Gq-mediated receptor signaling operably linked thereto, wherein said administration is effected under conditions such that said sequence is expressed, said peptide is produced and said treatment or prevention is thereby effected.  
     
     
         17 . The method according to  claim 16  wherein said promoter is a myocyte-specific promoter.  
     
     
         18 . The method according to  claim 16  wherein said construct is directly delivered to vasculature smooth muscle cells of said mammal.  
     
     
         19 . A construct comprising a myocyte-specific promoter and a nucleic acid sequence encoding a peptide that inhibits Gq-mediated receptor signaling operably linked thereto.  
     
     
         20 . The construct according to  claim 19  wherein said peptide corresponds to a carboxy terminal peptide of Gαq.  
     
     
         21 . The construct according to  claim 19  wherein said promoter is an a myosin heavy chain gene promoter.  
     
     
         22 . A composition comprising the construct according to  claim 19  and a pharmaceutically acceptable carrier.  
     
     
         23 . A transgenic non-human animal comprising cells expressing a peptide that inhibits Gq-mediated receptor signaling.  
     
     
         24 . The animal according to  claim 23  wherein said peptide corresponds to a carboxy terminal peptide of Gαq.  
     
     
         25 . The animal according to  claim 23  wherein said animal is a rodent.  
     
     
         26 . The animal according to  claim 23  wherein said cells are myocytes or vascular smooth muscle cells.  
     
     
         27 . An isolated host cell comprising a construct comprising a promoter and a nucleic acid sequence encoding a peptide that inhibits Gq-mediated receptor signaling operably linked thereto.  
     
     
         28 . The host cell according to  claim 27  wherein said host cell is a myocyte or vascular smooth muscle cell.  
     
     
         29 . The host cell according to  claim 27  wherein said promoter is a myocyte-specific promoter.  
     
     
         30 . A method of screening a compound for its ability to inhibit myocardial hypertrophy or vasculature smooth muscle cell proliferation or migration comprising assaying said compound for its ability to inhibit Gq-mediated receptor signaling, wherein a compound that inhibits said signaling has the aiblity to inhibit myocardial hypertrophy or vasculature smooth muscle cell proliferation or migration.  
     
     
         31 . A compound selected in accordance with the method of claim  30 .  
     
     
         32 . A composition comprising the compound of claim  31  and a pharmaceutically acceptable carrier.