Stabilization of hypoxia inducible factor (HIF) alpha

Abstract

The present invention relates to methods of stabilizing the alpha subunit of hypoxia inducible factor (HIF). The invention further relates to methods of preventing, pretreating, or treating conditions associated with HIF, including ischemic and hypoxic conditions. Compounds for use in these methods are also provided.

What is claimed is:  
     
         1 . A method for stabilizing the alpha subunit of hypoxia inducible factor (HIFα) in a subject, the method comprising administering a compound that inhibits hydroxylation of HIFα.  
     
     
         2 . A method for stabilizing the alpha subunit of hypoxia inducible factor (HIFα) in a subject, the method comprising administering to a compound that inhibits 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         3 . A method for stabilizing the alpha subunit of hypoxia inducible factor (HIFα) in a subject, the method comprising administering to a subject a compound that inhibits HIF prolyl hydroxylase enzyme activity.  
     
     
         4 . The method of  claim 1 , wherein HIFα is selected from the group consisting of HIF-1α, HIF-2α, HIF-3α, and any fragment thereof.  
     
     
         5 . The method of  claim 1 , wherein the HIFα is endogenous to the subject.  
     
     
         6 . The method of  claim 2 , wherein the 2-oxoglutarate dioxygenase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, procollagen prolyl 4-hydroxylase, procollagen prolyl 3-hydroxylase, procollagen lysyl hydroxylase, PHD4, FIH-1, and any subunit or fragment thereof.  
     
     
         7 . The method of  claim 3 , wherein the HIF prolyl hydroxylase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, and any subunit or fragment thereof.  
     
     
         8 . The method of  claim 1 , wherein the administering occurs in vivo.  
     
     
         9 . The method of  claim 8 , wherein the subject is an animal.  
     
     
         10 . The method of  claim 8 , wherein the subject is a mammal.  
     
     
         11 . The method of  claim 8 , wherein the subject is a human.  
     
     
         12 . The method of  claim 1 , wherein the administering occurs ex vivo.  
     
     
         13 . The method of  claim 12 , wherein the subject is selected from the group consisting of a cell, a tissue, and an organ.  
     
     
         14 . The method of  claim 13 , wherein the cell, tissue, or organ is derived from a system selected from the group consisting of the renal, cardiac, hepatic, pulmonary, hematopoietic, gastrointestinal, neuronal, and musculoskeletal systems.  
     
     
         15 . A method for treating, preventing, or pretreating a HIF-associated condition in a subject, the method comprising stabilizing HIFα.  
     
     
         16 . The method of  claim 15 , wherein the HIF-associated condition is associated with hypoxia.  
     
     
         17 . The method of  claim 15 , wherein the HIF-associated condition is associated with ischemia.  
     
     
         18 . A method for treating, preventing, or pretreating a HIF-associated condition in a subject, the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         19 . The method of  claim 18 , wherein the HIF-associated condition is associated with hypoxia.  
     
     
         20 . The method of  claim 18 , wherein the HIF-associated condition is associated with ischemia.  
     
     
         21 . A method for treating, preventing, or pretreating a HIF-associated condition in a subject, the method comprising inhibiting HIF prolyl hydroxylase enzyme activity.  
     
     
         22 . The method of  claim 21 , wherein the HIF-associated condition is associated with hypoxia.  
     
     
         23 . The method of  claim 21 , wherein the HIF-associated condition is associated with ischemia.  
     
     
         24 . The method of  claim 15 , wherein the HIF-associated condition is a pulmonary disorder.  
     
     
         25 . The method of  claim 15 , wherein the HIF-associated condition is a cardiac disorder.  
     
     
         26 . The method of  claim 15 , wherein the HIF-associated condition is a neurological disorder.  
     
     
         27 . The method of  claim 15 , wherein the HIF-associated condition is associated with an ischemic event.  
     
     
         28 . The method of  claim 27 , wherein the ischemic event is acute.  
     
     
         29 . The method of  claim 28 , wherein the ischemic event is associated with surgery, organ transplantation, infarction, trauma, or injury.  
     
     
         30 . The method of  claim 27 , wherein the ischemic event is chronic.  
     
     
         31 . The method of  claim 30 , wherein the ischemic event is associated with a condition selected from the group consisting of hypertension, diabetes, occlusive arterial disease, chronic venous insufficiency, Raynaud's disease, cirrhosis, congestive heart failure, and systemic sclerosis.  
     
     
         32 . The method of  claim 15 , wherein the method comprises administering to the subject a compound that stabilizes HIFα.  
     
     
         33 . The method of  claim 18 , wherein the method comprises administering to the subject a compound that inhibits 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         34 . The method of  claim 21 , wherein the method comprises administering to the subject a compound that inhibits HIF prolyl hydroxylase enzyme activity.  
     
     
         35 . The method of  claim 15 , wherein the method further comprises administering to the subject a second compound.  
     
     
         36 . The method of  claim 35 , wherein the second compound inhibits 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         37 . The method of  claim 35 , wherein the compound inhibits the activity of a first 2-oxoglutarate dioxygenase enzyme and the second compound inhibits the activity of a second 2-oxoglutarate dioxygenase enzyme.  
     
     
         38 . The method of  claim 35 , wherein the second compound is selected from the group consisting of an ACE inhibitor (ACEI), angiotensin-II receptor blocker (ARB), diuretic, digoxin, statin, or carnitine.  
     
     
         39 . The method of  claim 32 , wherein the compound stabilizes HUFα by specifically inhibiting hydroxylation of at least one amino acid residue in HIFα.  
     
     
         40 . The method of  claim 39 , wherein the amino acid residue is selected from the group consisting of proline and asparagine.  
     
     
         41 . A method for increasing expression of angiogenic factors in a subject, the method comprising stabilizing HTFα.  
     
     
         42 . A method for increasing expression of glycolytic factors in a subject, the method comprising stabilizing HIFα.  
     
     
         43 . A method for increasing expression of factors associated with oxidative stress in a subject, the method comprising stabilizing HIFα.  
     
     
         44 . A method of treating a subject having a disorder associated with ischemic reperfusion injury, the method comprising stabilizing HIFα.  
     
     
         45 . The method of  claim 1 , wherein the compound is selected from the group consisting of heterocyclic carboxamides, phenanthrolines, hydroxamates, and physiologically active salts and prodrugs derived therefrom.  
     
     
         46 . The method of  claim 45 , wherein the heterocyclic carboxamides are selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides.  
     
     
         47 . The method of  claim 1 , wherein the compound is delivered in an oral formulation.  
     
     
         48 . The method of  claim 1 , wherein the compound is delivered in a transdermal formulation.  
     
     
         49 . A method of identifying a compound that stabilizes HIFα the method comprising: 
 (a) administering a compound of interest to a subject or to a sample from a subject;  
 (b) measuring the HIFα level in the subject or in the sample; and  
 (c) comparing the HIFα level in the subject or in the sample to a standard level, wherein an increase in the HIFα level in the subject or the sample is indicative of a compound that stabilizes HIFα.