Compositions and methods for the treatment and prevention of cardiovascular diseases and disorders, and for identifying agents therapeutic therefor
View Patent ↗Methods and compositions are disclosed that are useful for the prevention and/or treatment of cardiovascular and cardiac diseases and disorders, or damage resulting from surgical or medical procedures that may cause ischemic or ischemic/reperfusion damage in humans; and cardiovascular trauma. The beneficial effects of the compositions and methods are achieved through the use of pharmaceutical compositions that include agents that interfere with the production and/or biological activities of sphingolipids and their metabolites, particularly sphingosine (SPH) and sphingosine-1-phosphate (S-1-P). Also disclosed are methods for identifying and isolating therapeutic agents.
1. A nucleic acid having the nucleotide sequence SEQ ID NO:3.
2. A polypeptide encoded by the nucleic acid of claim 1 .
3. A nucleic acid having the nucleotide sequence SEQ ID NO:4.
4. A polypeptide encoded by the nucleic acid of claim 3 .
5. A nucleic acid having the nucleotide sequence SEQ ID NO:7.
6. A polypeptide encoded by the nucleic acid of claim 5 .
7. An expression construct comprising a nucleic acid having a sequence selected from the group consisting of SEQ ID NOS: 3, 4, and 7.
8. A host cell comprising the expression construct of claim 7 .
9. A method of producing a polypeptide, comprising culturing the host cell of claim 8 .
10. An expression construct comprising a portion of a nucleic acid having a portion of sequence selected from the group consisting of SEQ ID NO:3 wherein said portion of said sequence lacks nucleotide sequences that encode a transmembrane domain of a polypeptide encoded thereby.
11. An expression construct comprising a portion of a nucleic acid having a portion of sequence selected from the group consisting of SEQ ID NO:4 wherein said portion of said sequence lacks nucleotide sequences that encode a transmembrane domain of a polypeptide encoded thereby.
12. An expression construct comprising a portion of a nucleic acid having a portion of sequence selected from the group consisting of SEQ ID NO:7 wherein said portion of said sequence lacks nucleotide sequences that encode a transmembrane domain of a polypeptide encoded thereby.
13. A host cell comprising the expression vector of claim 10 .
14. A host cell comprising the expression vector of claim 11 .
15. A host cell comprising the expression vector of claim 12 .
16. A method of producing a soluble receptor fragment, comprising culturing the host cell of claim 11 .
17. A method of producing a soluble receptor fragment, comprising culturing the host cell of claim 12 .
18. A method of producing a soluble receptor fragment, comprising culturing the host cell of claim 13 .
19. A soluble receptor fragment, derived from a receptor selected from the group consisting of Edg-1, Edg-3, Edg-5, Edg-6, Edg-8, the Mil receptor, AXOR29, NRG1, SCaMPER and homologs and isoforms thereof.
20. A method of screening for an agent for treating or preventing cardiovascular or cerebrovascular disease, comprising screening a library of compounds for agents that bind a receptor for sphingolipid or a sphingolipid metabolite.
21. The method of claim 18 wherein said receptor is selected from the group consisting of Edg-1, Edg-3, Edg-5, Edg-6, Edg-8, the Mil receptor, AXOR29, NRG1, SCaMPER and homologs and isoforms thereof.
22. The method of claim 18 wherein said receptor is encoded by SEQ ID NO:3, SEQ ID NO: 4, or SEQ ID NO:7.