Unacylated ghrelin and analogs as therapeutic agents for vascular remodeling in diabetic patients and treatment of cardiovascular disease

Abstract

The present invention relates to a method for treating a cardiovascular disease, for increasing the number of circulating angiogenic cells (CAC) and/or improving the function of CAC and a method for improving vascular remodeling and/or neovascularisation. The method comprises administering to the subject a therapeutically effective amount of unacylated ghrelin or a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or a fragment or analog thereof having the biological activity of SEQ ID NO: 1; and to pharmaceutical compositions comprising unacylated ghrelin or a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or a fragment or analog thereof having the biological activity of SEQ ID NO: 1.

1 . A method for treating a cardiovascular disease in a subject, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or a fragment or analog thereof having the biological activity of SEQ ID NO: 1. 
     
     
         2 . The method of  claim 1 , wherein the method is for improving vascular remodeling and/or neovascularization. 
     
     
         3 . The method of  claim 1 , wherein the method is for increasing the number of circulating angiogenic cells (CAC) and/or improving the function of CAC. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 3 , wherein the method is for improving CAC mobilization. 
     
     
         6 . The method of  claim 3 , wherein the method is for reducing CAC senescence. 
     
     
         7 . The method of  claim 1 , wherein the polypeptide is administered in a dose varying from about 0.001 μg/kg to about 10 mg/kg. 
     
     
         8 . The method of  claim 1 , wherein the cardiovascular disease is associated with type I or type II diabetes. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the cardiovascular disease is associated with atherosclerotic vascular degeneration. 
     
     
         12 . The method of  claim 1 , wherein the fragment thereof comprises amino acid residues selected from the group consisting of amino acid residues 8 to 12 of SEQ ID NO: 1 or an analog thereof and amino acid residues 6 to 13 of SEQ ID NO: 1 or an analog thereof. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the fragment thereof has an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8 and analogs thereof. 
     
     
         15 . The method  claim 1 , wherein the fragment thereof consists of amino acid sequence SEQ ID NO: 6. 
     
     
         16 . (canceled) 
     
     
         17 . A method for increasing the number of circulating angiogenic cells (CAC) and/or improving the function of CAC in a subject, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1, or a fragment or analog thereof having the biological activity of SEQ ID NO: 1. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 17 , wherein the method is for improving CAC mobilization. 
     
     
         20 . The method of  claim 17 , wherein the method is for reducing CAC senescence. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 17 , wherein the subject is at risk of having or has a cardiovascular disease. 
     
     
         23 . The method of  claim 17 , wherein the subject has type I or type II diabetes. 
     
     
         24 . The method of  claim 17 , wherein the polypeptide is administered in a dose varying from about 0.001 μg/kg to about 10 mg/kg. 
     
     
         25 . The method of  claim 17 , wherein the fragment thereof comprises residues 8 to 12 of SEQ ID NO: 1 or an analog thereof. 
     
     
         26 . The method of  claim 17 , wherein the fragment thereof comprises residues 6 to 13 of SEQ ID NO: 1 or an analog thereof. 
     
     
         27 . (canceled) 
     
     
         28 . The method  claim 17 , wherein the fragment thereof consists of amino acid sequence SEQ ID NO: 6. 
     
     
         29 . A method for improving vascular remodeling and/or neovascularization in a subject comprising administering to the subject a therapeutically effective amount of a polypeptide comprising the sequence set forth in SEQ ID NO: 1, or a fragment or analog thereof having the biological activity of SEQ ID NO: 1. 
     
     
         30 . The method of  claim 29 , wherein the method is for increasing the number of circulating angiogenic cells (CAC) and/or improving the function of CAC. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 29 , wherein the fragment thereof comprises amino acid residues selected from the group consisting of amino acid residues 8 to 12 of SEQ ID NO: 1 or an analog thereof and amino acid residues 6 to 13 of SEQ ID NO: 1 or an analog thereof. 
     
     
         33 - 44 . (canceled) 
     
     
         45 . The method of  claim 29 , for improving wound healing in the subject. 
     
     
         46 . The method of  claim 29 , for treating a venous or a diabetic ulcer in the subject. 
     
     
         47 . The method of  claim 29 , for improving engraftment associated with organ transplantation.