Regeneration of endogenous myocardial tissue by induction of neovascularization

Abstract

This invention provides a method of treating a disorder of a subject's heart involving loss of cardiomyocytes which comprises administering to the subject an amount of an agent effective to cause cardiomyocyte proliferation within the subject's heart so as to thereby treat the disorder. This invention further provides the instant method wherein the agent is human endothelial progenitor cells. This invention also provides methods of determining the susceptibility of a cardiomyocyte in a subject to apoptosis.

What is claimed is:  
     
         1 . A method of treating a disorder of a subject's heart involving loss of cardiomyocytes which comprises administering to the subject an amount of an agent effective to cause cardiomyocyte proliferation within the subject's heart so as to thereby treat the disorder.  
     
     
         2 . The method of  claim 1 , wherein the agent is human endothelial progenitor cells.  
     
     
         3 . The method of  claim 2  which further comprises administering an effective amount of a second agent that increases the cardiomyocyte proliferation caused by the human endothelial progenitor cells.  
     
     
         4 . The method of  claim 3 , wherein the agent is an antisense oligonucleotide which specifically inhibits translation of Vitamin D3 Up-Regulated Protein-1 (VDUP-1) mRNA.  
     
     
         5 . The method of  claim 3 , wherein the agent is a catalytic nucleic acid which specifically inhibits translation of Vitamin D3 Up-Regulated Protein-1 mRNA.  
     
     
         6 . The method of  claim 5 , wherein the catalytic nucleic acid comprises deoxyribonucleotides.  
     
     
         7 . The method of  claim 5 , wherein the catalytic nucleic acid comprises ribonucleotides.  
     
     
         8 . The method of  claim 3 , wherein the second agent is a pro-angiogenic agent.  
     
     
         9 . The method of  claim 8 , wherein the pro-angiogenic agent is vascular endothelial growth factor, fibroblast growth factor or angiopoietin.  
     
     
         10 . The method of  claim 3 , wherein the second agent induces expression of a pro-angiogenic factor.  
     
     
         11 . The method of  claim 10 , wherein the second agent is Hypoxia Inducible Factor-1.  
     
     
         12 . The method of  claim 3 , wherein the second agent promotes trafficking of the endothelial progenitor cells to the subject's heart.  
     
     
         13 . The method of  claim 12 , wherein the second agent that promotes trafficking is an antibody directed against an epitope of CXCR4.  
     
     
         14 . The method of  claim 12 , wherein the second agent that promotes trafficking is a CC chemokine.  
     
     
         15 . The method of  claim 14 , wherein the CC chemokine is RANTES, EOTAXIN, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, or MCP.  
     
     
         16 . The method of  claim 12 , wherein the second agent is a CXC chemokine.  
     
     
         17 . The method of  claim 16 , wherein the CXC chemokine is Interleukin-8, Gro-Alpha, or Stromal-Derived Factor-1.  
     
     
         18 . The method of  claim 3 , wherein the second agent is cardiomyocyte progenitor cells.  
     
     
         19 . The method of  claim 3 , wherein the second agent is skeletal muscle progenitor cells.  
     
     
         20 . The method of  claim 2 , wherein the effective amount of human endothelial progenitor cells is between 2.5×10 5  and 7.5×10 5  endothelial progenitor cells per kg of the subject's body mass.  
     
     
         21 . The method of  claim 20 , wherein the effective amount is 5×10 5  endothelial progenitor cells per kg of the subject's body mass.  
     
     
         22 . The method of  claim 2 , wherein the endothelial progenitor cells are allogeneic with respect to the subject.  
     
     
         23 . The method of  claim 22 , wherein the subject is an adult.  
     
     
         24 . The method of  claim 22 , wherein the subject is an embryo or a fetus.  
     
     
         25 . The method of  claim 2 , wherein the administering comprises injecting directly into the subject's peripheral circulation, heart muscle, left ventricle, right ventricle, coronary artery, cerebro-spinal fluid, neural tissue, ischemic tissue, or post-ischemic tissue.  
     
     
         26 . The method of  claim 2 , wherein the human endothelial progenitor cells express CD117, CD34 or AC133.  
     
     
         27 . The method of  claim 2 , wherein endothelial progenitor cells express a high level of intracellular GATA-2 activity.  
     
     
         28 . The method of  claim 1 , wherein the agent induces expression of a mRNA encoding a peroxiredoxin.  
     
     
         29 . The method of  claim 28 , wherein the agent is 2(3)-t-butyl-4-hydroxyanisole.  
     
     
         30 . The method of  claim 1 , wherein the agent induces expression of a mRNA encoding NF-E2-related factor 2 (Nrf2).  
     
     
         31 . The method of  claim 1 , wherein the agent induces dissociation of a Nrf2 protein from a Keap-1.  
     
     
         32 . The method of  claim 1 , wherein the agent inhibits association of a Nrf2 protein with a Keap-1.  
     
     
         33 . The method of  claim 1 , wherein the agent inhibits association of a thiol reductase thioredoxin with a VDUP-1 protein.  
     
     
         34 . The method of  claim 1 , wherein the agent inhibits c-Abl tyrosine kinase activation.  
     
     
         35 . The method of  claim 34 , wherein the agent is STI-571.  
     
     
         36 . The method of  claim 1 , wherein the agent is a CXC chemokine.  
     
     
         37 . The method of  claim 36 , wherein the chemokine is Stromal-Derived Factor-1, Il-8 or Gro-Alpha.  
     
     
         38 . The method of  claim 1 , wherein the agent is an inhibitor of plasminogen activator inhibitor-1.  
     
     
         39 . The method of  claim 1 , wherein the agent is an antibody directed against an epitope of CXCR4.  
     
     
         40 . The method of  claim 1 , wherein the subject has a cardiovascular disease.  
     
     
         41 . The method of  claim 40 , wherein the subject has congestive heart failure.  
     
     
         42 . The method of  claim 40 , wherein the subject has suffered a myocardial infarct.  
     
     
         43 . The method of  claim 40 , wherein the subject has suffered myocardial ischemia.  
     
     
         44 . The method of  claim 40 , wherein the subject has angina.  
     
     
         45 . The method of  claim 40 , wherein the subject has a cardiomyopathy.  
     
     
         46 . The method of  claim 1 , wherein the subject is a mammal.  
     
     
         47 . The method of  claim 46 , wherein the mammal is a human being.  
     
     
         48 . A method of determining the susceptibility of a cardiomyocyte in a subject to apoptosis comprising: 
 (a) quantitating the amount of mRNA encoding peroxiredoxin in the cardiomyocyte;    (b) quantitating the amount of mRNA encoding Vitamin D3 Up-Regulated Protein-1 in the cardiomyocyte; and    (c) determining the ratio of the amount of mRNA encoding peroxiredoxin: amount of mRNA encoding Vitamin D3 Up-Regulated Protein-1, wherein a low ratio indicates a high susceptibility of the cardiomyocyte to apoptosis and a high ratio indicates a low susceptibility of the cardiomyocyte to apoptosis in the subject.    
     
     
         49 . A method of determining the susceptibility of a cardiomyocyte in a subject to apoptosis comprising: 
 (a) quantitating the expression of a peroxiredoxin protein in the cardiomyocyte;    (b) quantitating the expression of Vitamin D3 Up-Regulated Protein-1 in the cardiomyocyte; and    (c) determining the ratio of the peroxiredoxin protein expression: Vitamin D3 Up-Regulated Protein-1 expression, wherein a low ratio indicates a high susceptibility of the cardiomyocyte to apoptosis and a high ratio indicates a low susceptibility of the cardiomyocyte to apoptosis in the subject.