SUMOYLATION OF SERCA2a AND CARDIOVASCULAR DISEASE
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 . A method of treating cardiac dysfunction in a subject comprising administering a therapeutically effective amount of a modulator of SERCA2a post-translational modification to the subject.
2 . The method according to claim 1 wherein the cardiac dysfunction is selected from the group consisting of heart failure, pressure overload-induced cardiac dysfunction, and cardiac dysfunction induced by inhibited calcium decay.
3 . The method according to claim 2 wherein the heart failure comprises contractile dysfunction.
4 . The method according to claim 2 wherein the heart failure is TAC-induced heart failure.
5 . The method according to claim 1 wherein the subject is a human.
6 . The method according to claim 1 wherein the modulator modulates SERCA2a post-translational SUMOylation.
7 . The method according to claim 6 wherein the modulator is a vector comprising an expressible coding region encoding a protein selected from the group consisting of SERCA2a and SUMO1, and wherein the coding region is operably linked to at least one expression control element.
8 . The method according to claim 7 wherein the vector is a recombinant adeno-associated virus.
9 . The method according to claim 8 wherein the recombinant adeno-associated virus is rAAV1.
10 . The method according to claim 1 wherein the modulator modulates SERCA2a post-translational acetylation.
11 . The method according to claim 10 wherein the modulator is Sirtl deacetylase.
12 . A method of treating a cardiovascular disorder in a subject by inhibiting SERCA2a degradation comprising administering a therapeutically effective amount of a SUMO1 agent.
13 . The method according to claim 12 wherein the SUMO1 agent is a vector comprising an expressible coding region encoding a protein selected from the group consisting of SERCA2a and SUMO1, and wherein the coding region is operably linked to at least one expression control element.
14 . The method according to claim 13 wherein the vector is recombinant adeno-associated virus.
15 . The method according to claim 14 wherein the recombinant adeno-associated virus is rAAV1.
16 . A method of diagnosing a propensity to develop heart failure comprising determining the amino acid corresponding to a position selected from the group consisting of any of positions 479-482 and/or position 584-587 of human SERCA2a (SEQ ID NO:2).
17 . A method of diagnosing a propensity to develop heart failure comprising determining the polynucleotide sequence encoding an amino acid corresponding to any of amino acids 479-482 or 584-587 of human SERCA2a (SEQ ID NO:1).
18 . A method of diagnosing a propensity to develop heart failure comprising determining the level of expression of SUMO1 in a cardiomyocyte of a 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 . A method of screening for a therapeutic to treat heart failure comprising contacting SUMO1 and SERCA2a in the presence and absence of a candidate therapeutic and identifying the candidate therapeutic as a therapeutic if the level of SERCA2a SUMOylation is greater in the presence compared to the absence of the candidate therapeutic.