Method of treating endothelial dysfunction

Abstract

Endothelial dysfunction (ED) is associated with a number of diseases and disorders. Agonists of the non-proteolytically activated thrombin receptor can be used in methods to treat ED or ED-related diseases and disorders.

1 - 81 . (canceled) 
     
     
         82 . A method of treating peripheral vascular disease in a subject comprising administering to the subject a therapeutically effective amount of a 12 to 23 amino acid thrombin peptide derivative comprising a serine esterase conserved sequence and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO:16). 
     
     
         83 . The method of  claim 82 , wherein the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2  and the thrombin peptide derivative comprises a polypeptide having the amino sequence of Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:1), wherein X 1  is Glu or Gln and X 2  is Phe, Met, Leu, His or Val. 
     
     
         84 . The method of  claim 82 , wherein the thrombin peptide derivative comprises the amino acid sequence of Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO:2, wherein X 1  is Glu or Gln and X 2  is Phe, Met, Leu, His or Val and the thrombin peptide derivative comprises an N-terminus which is unsubstituted and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 . 
     
     
         85 . A method of treating peripheral vascular disease in a subject comprising administering to the subject a therapeutically effective amount of the polypeptide H-Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-NH 2  (SEQ ID NO:3). 
     
     
         86 . A method of treating peripheral vascular disease in a subject comprising administering to the subject a peptide dimer comprising two 12 to 23 amino acid thrombin peptide derivatives which, independently, comprise a serine esterase conserved sequence and a thrombin binding domain having the sequence Arg-Gly-Asp-Ala (SEQ ID NO:16). 
     
     
         87 . The method of  claim 86 , wherein the dimer is essentially free of monomer. 
     
     
         88 . The method of  claim 86 , wherein the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 . 
     
     
         89 . The method of  claim 86 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1  is Glu or Gln and X 2  is Phe, Met, Leu, His or Val, or a fragment thereof, comprising amino acids 10-18 of SEQ ID NO:2, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted, and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 , the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond. 
     
     
         90 . The method of  claim 86 , wherein the thrombin peptide derivatives each comprise the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1  is Glu or Gln and X 2  is Phe, Met, Leu, His or Val, the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 , the dimer is essentially free of monomer; the thrombin peptide derivatives are the same, and the thrombin peptide derivatives are covalently linked through a disulfide bond. 
     
     
         91 . The method of  claim 90 , wherein X 1  is Glu and X 2  is Phe. 
     
     
         92 . The method of  claim 86 , wherein the peptide dimer comprises two thrombin peptide derivatives, each with the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val (SEQ ID NO:6), wherein the thrombin peptide derivatives are covalently linked by a disulfide bond. 
     
     
         93 . A method of treating peripheral vascular disease in a subject comprising administering to the subject a peptide dimer represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         94 . The method of  claim 82 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor. 
     
     
         95 . The method of  claim 85 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor. 
     
     
         96 . The method of  claim 86 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor. 
     
     
         97 . The method of  claim 93 , wherein the method further comprises administering to the subject a therapeutically effective amount of an angiogenic growth factor.