Atherosclerosis susceptibility gene locus 1(athsq1) and atherosclerosis susceptibility gene locus 2 (athsq2)

Abstract

This invention provides isolated nucleic acids encoding mammalian membrane-bound and soluble LOX-1 receptors. The invention also provides methods of identifying agents that inhibit the activity of a mammalian LOX-1 receptor. This invention further provides methods of preventing or treating atherosclerosis, heart disease or stroke in a subject which comprise reducing the activity of membrane-bound LOX-1 receptor.

What is claimed is:  
     
         1 . An isolated nucleic acid encoding a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO: 18, SEQ ID NO:22, SEQ ID NO:24, and SEQ ID. NO:26.  
     
     
         2 . The nucleic acid of  claim 1 , wherein the nucleic acid has a sequence selected from the group consisting of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, and SEQ ID NO:28.  
     
     
         3 . The nucleic acid of  claim 1 , wherein the nucleic acid is DNA or RNA.  
     
     
         4 . The nucleic acid of  claim 3 , wherein the DNA is cDNA.  
     
     
         5 . A nucleic acid probe of at least about 15 nucleotides in length which specifically hybridizes with a nucleic acid encoding a mammalian LOX-1 receptor or with a nucleic acid having the complementary sequence thereof.  
     
     
         6 . The nucleic acid probe of  claim 5 , wherein the mammalian LOX-1 receptor has an amino acid sequence selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO: 18, SEQ ID NO:22, SEQ ID NO:24, and SEQ ID NO:26.  
     
     
         7 . The nucleic acid probe of  claim 5 , wherein the probe specifically hybridizes with a nucleic acid encoding the amino acid sequence shown in SEQ ID NO:39.  
     
     
         8 . The nucleic acid probe of  claim 5 , wherein the probe is labeled with a detectable marker.  
     
     
         9 . An isolated protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO: 18, SEQ ID NO:22, SEQ ID NO:24, and SEQ ID NO:26.  
     
     
         10 . A vector comprising the nucleic acid of  claim 1 .  
     
     
         11 . The vector of  claim 10 , wherein the vector is adapted for expression of the nucleic acid in a cell and comprises regulatory elements necessary for expression of the nucleic acid in the cell operatively linked to the nucleic acid so as to permit expression thereof.  
     
     
         12 . A cell comprising the vector of  claim 10 .  
     
     
         13 . The cell of  claim 12 , wherein the cell is a bacterial, amphibian, yeast, fungal, insect, plant, or mammalian cell.  
     
     
         14 . The cell of  claim 12 , wherein but for the vector present therein, the cell would not express a mammalian LOX-1 receptor.  
     
     
         15 . A method of determining whether an agent inhibits the activity of a membrane-bound mammalian LOX-1 receptor, which comprises (a) contacting the agent with the receptor under conditions which would permit the inhibition of such activity by an activity-inhibiting agent, and (b) detecting whether the agent has inhibited the activity of the LOX-1 receptor.  
     
     
         16 . The method of  claim 15 , wherein the LOX-1 receptor is a mouse receptor.  
     
     
         17 . The method of  claim 15 , wherein the LOX-1 receptor is a human receptor.  
     
     
         18 . An agent determined by the method of  claim 15  to inhibit the activity of a membrane-bound mammalian LOX-1 receptor.  
     
     
         19 . A composition which comprises the agent of  claim 18  and a pharmaceutically acceptable carrier.  
     
     
         20 . A method of preparing a composition which comprises identifying an agent by the method of  claim 15 , recovering the agent free of LOX-1 receptor, and admixing the agent with a pharmaceutically acceptable carrier.  
     
     
         21 . A method of inhibiting the activity of a mammalian. LX-1 receptor, which comprises contacting the receptor with an agent that inhibits the activity of a mammalian LOX-1 receptor.  
     
     
         22 . The method of  claim 21 , wherein the LOX-1 receptor, is membrane-bound.  
     
     
         23 . A method of reducing the amount of a mammalian LOX-1 receptor on the surface of a cell, which comprises delivering to the cell an agent that reduces the expression of mamma lian LOX-1 receptor therein.  
     
     
         24 . The method of  claim 23 , wherein the agent is a catalytic nucleic acid or an antisense nucleic acid.  
     
     
         25 . A method of inhibiting the ability of an agent to bind to and activate a membrane-bound mammalian LOX-1 receptor, which comprises contacting the agent with a soluble mammalian LOX-1 receptor.  
     
     
         26 . A method of treating a mammalian subject afflicted with a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a therapeutically effective amount of an agent that inhibits the activity of LOX-1 receptors in the subject.  
     
     
         27 . A method of inhibiting the onset in a mammalian subject of a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a prophylactically effective amount of an agent that inhibits the activity of LOX-1 receptors in the subject.  
     
     
         28 . A method of treating a mammalian subject afflicted with a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a therapeutically effective amount of an agent that inhibits the expression of LOX-1 receptors in the subject's cells.  
     
     
         29 . A method of inhibiting the onset in a mammalian subject of a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a prophylactically effective amount of an agent that inhibits the expression of LOX-1 receptors in the subject's cells.  
     
     
         30 . A method of treating a mammalian subject afflicted with a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a therapeutically effective amount of a soluble LOX-1 receptor.  
     
     
         31 . A method of inhibiting the onset in a mammalian subject of a disorder selected from the group consisting of atherosclerosis, heart failure and stroke, comprising administering to the subject a prophylactically effective amount of a soluble LOX-1 receptor.  
     
     
         32 . The method of  claim 26 ,  27 ,  28 ,  29 ,  30 , or  31 , wherein the disorder is atherosclerosis.  
     
     
         33 . The method of  claim 26 ,  27 ,  28 ,  29 ,  30 , or  31 , wherein the disorder is heart failure.  
     
     
         34 . The method of  claim 26 ,  27 ,  28 ,  29 ,  30 , or  31 , wherein the disorder is stroke.  
     
     
         35 . The method of  claim 26 ,  27 ,  28 ,  29 ,  30 , or  31 , wherein the subject is a mouse.  
     
     
         36 . The method of  claim 26 ,  27 ,  28 ,  29 ,  30 , or  31 , wherein the subject is a human.  
     
     
         37 . A method of inhibiting binding of a ligand to a membrane bound receptor in a mammalian subject which comprises administering to the subject an amount of a soluble LOX-1 receptor effective to bind the ligand and inhibit binding of the ligand to the membrane bound receptor, wherein the membrane bound receptor is LOX-1 receptor, CD-36 receptor, or scavenger receptor A, and wherein the ligand is oxidized lipoprotein or an advanced glycation end product.  
     
     
         38 . The method of  claim 37 , wherein the method is effective to treat a disorder selected from the group consisting of atherosclerosis, heart failure, stroke, and inflamation.  
     
     
         39 . Use of soluble LOX-1 for the preparation of a composition for treating an abnormality.  
     
     
         40 . Use of an agent that inhibits the activity of a membrane-bound LOX-1 receptor for the preparation of a composition for treating an abnormality.  
     
     
         41 . The use of  claim 39  or  40 , wherein the abnormality is atherosclerosis, heart failure, stroke, or inflamation.  
     
     
         42 . The use of any of claims 39-41, wherein the preparation step comprises admixing soluble LOX-1 or the agent with a carrier.