Sumoylation of Serca2A and Cardiovascular Disease

Abstract

Methods for treating cardiovascular disease, and in particular heart failure, are provided comprising administering a therapeutically effective amount of a modulator of SERCA2a post-translation modification such as SUMOylation or acetylation. Also provided are methods of treating cardiovascular disease by inhibiting SERCA2a degradation. Further provided are methods of diagnosing a propensity to develop heart failure comprising determining if a SERCA2a mutant is present or determining the level of expression of SUMO1 in cardiomyocytes. The disclosure also provides methods of screening for therapeutics that modulate the post-translational modification of SERCA2a, such as by modulating post-translational SUMOylation and/or acetylation.

1 .- 17 . (canceled) 
     
     
         18 . A method of diagnosing a subject's propensity to develop heart failure, comprising determining the level of expression of SUMO1 in a cardiomyocyte of the subject and comparing that level to the level of expression of SUMO1 in a cardiomyocyte of a healthy control, wherein reduced expression of SUMO1 relative to the control is indicative of a propensity to develop cardiac failure. 
     
     
         19 . (canceled) 
     
     
         20 . A method of diagnosing a patient's disposition towards a cardiovascular disease, comprising (a) obtaining a biological sample from a patient, (b) determining the amino acid sequence of SERCA2a at one or more positions 479-482 and/or one or more positions 584-587, and (c) diagnosing a disposition towards cardiovascular disease if the amino acid sequence varies from the wild-type sequence of SERCA2a (SEQ ID NO: 2). 
     
     
         21 . The method of  claim 20 , wherein step b is carried out by determining the polynucleotide sequence encoding the amino acid sequence of SERCA2a at the position(s). 
     
     
         22 . The method of  claim 20 , wherein the cardiovascular disease is heart failure. 
     
     
         23 . A method of diagnosing a subject's propensity to develop heart failure, comprising (a) determining the expression level of SERCA2a, the level of SUMOylation of SERCA2a, or a combination thereof, in a cardiomyocyte of a subject and (b) comparing that level to a control level of a healthy subject, wherein reduced expression of SERCA2a, reduced SUMOylation of SERCA2a, or a combination thereof, relative to the control is indicative of a propensity to develop cardiac failure. 
     
     
         24 . The method of  claim 23 , further comprising determining the subject level of SERCA2a ATPase activity, SERCA2a stability, or a combination thereof. 
     
     
         25 . The method of  claim 18 , further comprising treating the subject for the heart failure. 
     
     
         26 . The method of  claim 20 , further comprising treating the subject for the cardiovascular disease. 
     
     
         27 . The method of  claim 23 , further comprising treating the subject for the heart failure.