Inhibitors and methods of treatment of cardiovascular diseases, and methods for identifying inhibitors

Abstract

The present invention provides, inter alia, inhibitors of cardiovascular diseases and disorders. The present invention also provides therapeutic methods for preventing and/or treating cardiovascular diseases and disorders. Further, the present invention provides methods of identifying inhibitors of cardiovascular diseases and disorders as well as model systems suitable for identifying such inhibitors as well as methods and compositions for detecting and/or diagnosing cardiovascular diseases and disorders.

1 .- 16 . (canceled) 
     
     
         17 . A method of developing a prognosis for a subject who has been diagnosed with a cardiovascular disease or disorder comprising measuring levels of DP1 and/or DP2 in a sample from the subject and comparing the DP1 and/or DP2 levels to the DP1 and/or DP2 levels found in control subjects. 
     
     
         18 . A method of identifying subjects at risk for aneurysm comprising measuring levels of DP1 and/or DP2 in a sample from a subject and comparing the DP1 and/or DP2 levels to DP1 and/or DP2 levels found in normal subjects, wherein elevated levels of DP1 and/or DP2 are indicative of an increased risk for aneurysm. 
     
     
         19 . The method of  claim 17  wherein DP1 and/or DP2 levels are measured in the media lamina or the intima of a vessel. 
     
     
         20 . A method of imaging one or more aneurysms in a subject comprising:
 a) administering a probe, antibody or fragment thereof, or oligonucleotide that specifically binds to a DP1 or a DP2 receptor into the subject's vasculature;   b) determining whether the probe, antibody or fragment thereof or oligonucleotide binds to the vasculature, wherein binding of the antibody to the vasculature is indicative of the presence of one or more aneurysms.   
     
     
         21 . The method of  claim 20  comprising:
 a) administering an antibody or fragment thereof, human monoclonal antibody fragment, or single chain fragment into the subject's vasculature, wherein the antibody specifically binds DP-1 or DP-2; and 
 b) determining whether the antibody or fragment thereof, human monoclonal antibody fragment, or single chain fragment binds to the vasculature, wherein binding of the antibody or fragment thereof, human monoclonal antibody fragment, or single chain fragment to the vasculature is indicative of the presence of one or more aneurysms. 
 
     
     
         22 . The method of  claim 20  wherein the antibody is a monoclonal antibody. 
     
     
         23 . The method of  claim 20  wherein the antibody is detectably labeled. 
     
     
         24 . The method of  claim 20  wherein the antibody binds to the media lamina or the intima of the vasculature. 
     
     
         25 . The method of  claim 20  wherein the imaging method is used to monitor the progression or regression of a cardiovascular disease or disorder. 
     
     
         26 . The method of  claim 20  wherein said subject is a human having or suspected of having atherosclerotic disease. 
     
     
         27 . The method of  claim 20  wherein the imaging method is used to monitor the progression or regression of an aneurysm. 
     
     
         28 . The method of  claim 20  wherein the subject is a human having or suspected of having one or more aneurysms. 
     
     
         29 . A method of inhibiting a cardiovascular disease or disorder in a subject in need thereof comprising administering to said patient an amount of a DP1 and/or DP2 receptor inhibitor effective to reduce collagen disruption in a vessel of the subject and/or an amount of a DP1 and/or DP2 receptor inhibitor effective to reduce elastin disruption in a vessel of the subject. 
     
     
         30 . A method of inhibiting an aneurysm in a subject in need thereof comprising administering to the subject a therapeutically effective dose of one or more compounds selected from the group consisting of: PGD2 receptor inhibitors, inhibitors of MAP Kinase activation; MAP Kinase inhibitors; inhibitors of cytokine expression; and inhibitors of smooth muscle cell proliferation. 
     
     
         31 . A method of inhibiting a symptom of aneurysm in a subject in need thereof comprising administering to the subject a therapeutically effective dose of one or more compounds selected from the group consisting of: PGD2 receptor inhibitors, Map Kinase inhibitors, inhibitors of Map kinase activation, DP1 and/or DP2 receptor inhibitors, and inhibitors of cytokine expression. 
     
     
         32 . The method of  claim 30  comprising administering to the subject a therapeutically effective dose of an inhibitor of cytokine expression; wherein the cytokine is selected from the group consisting of IL-1, IL-6, IL-8, IL-11, TNF-α, IFN-α, IFN-β, and TGF-β. 
     
     
         33 . The method of  claim 32  wherein expression of the cytokine is reduced by at least 50%. 
     
     
         34 . A method of inhibiting smooth muscle cell proliferation comprising in a subject in need thereof comprising administering to said patient a therapeutically effective amount of one or more compounds selected from the group consisting of: DP1 receptor antagonists, DP2 receptor antagonists and Map Kinase inhibitors. 
     
     
         35 . A method for reducing blood pressure in a subject comprising administering to said subject a therapeutically effective dose of one or more compounds selected from the group consisting of: PGD2 receptor inhibitors, Map Kinase inhibitors, inhibitors of Map kinase activation, DP1 and/or DP2 receptor inhibitors, and inhibitors of cytokine expression. 
     
     
         36 . The method of  claim 18  wherein DP1 and/or DP2 levels are measured in the media lamina or the intima of a vessel. 
     
     
         37 . The method of  claim 31  comprising administering to the subject a therapeutically effective dose of an inhibitor of cytokine expression; wherein the cytokine is selected from the group consisting of IL-1, IL-6, IL-8, IL-11, TNF-α, IFN-α, IFN-β, and TGF-β. 
     
     
         38 . The method of  claim 37  wherein expression of the cytokine is reduced by at least 50%.