Hypoxia-induced mitogenic factor

Abstract

We found that FIZZ1/RELMα is inducible by hypoxia in lung. The hypoxia-upregulated expression of FIZZ1/RELMα was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes. Recombinant FIZZ1/RELMα protein stimulates rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 inhibits HIMF-activated Akt phosphorylation. It also inhibits HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. HIMF also has angiogenic and vasoconstrictive activity. Notably, HIMF increases pulmonary arterial pressure and vascular resistance more potently than either endothelin-I or angiotensin II.

We claim: 
     
         1 . A method of treating a patient with pulmonary hypertension, comprising:
 administering to the patient an antibody which specifically binds to a protein comprising the sequence of SEQ ID NO: 1, in an amount sufficient to reduce the extent of pulmonary vasoconstriction.   
     
     
         2 . A method of promoting wound healing in a patient with a wound, comprising:
 administering a wound-healing amount of a HIMF protein comprising the amino acid sequence shown in SEQ ID NO: 1 to a patient in need thereof.   
     
     
         3 . The method of  claim 2  wherein the HIMF is administered locally to the wound. 
     
     
         4 . The method of  claim 2  wherein the HIMF is administered subcutaneously. 
     
     
         5 . The method of  claim 2  wherein the HIMF is administered intravenously. 
     
     
         6 . The method of  claim 2  wherein the wound in the lung. 
     
     
         7 . The method of  claim 2  wherein the wound in the heart. 
     
     
         8 . The method of  claim 2  wherein the wound is the result of injury. 
     
     
         9 . The method of  claim 2  wherein the wound is the result of surgery. 
     
     
         10 . The method of  claim 2  wherein the HIMF protein is mature HIMF protein of SEQ ID NO: 1. 
     
     
         11 . A method of promoting wound healing in a patient with a wound, comprising:
 administering a wound-healing amount of an expression construct that encodes HIMF (SEQ ID NO: 1) to a patient in need thereof.   
     
     
         12 . The method of  claim 11  wherein the construct encodes HIMF precursor protein of SEQ ID NO: 2. 
     
     
         13 . The method of  claim 11  wherein the expression construct comprises the nucleotide sequence of SEQ ID NO: 3. 
     
     
         14 . The method of  claim 11  wherein the expression construct is administered locally to the wound. 
     
     
         15 . The method of  claim 11  wherein the expression construct is administered subcutaneously. 
     
     
         16 . The method of  claim 11  wherein the wound is the result of surgery. 
     
     
         17 . The method of  claim 11  wherein the wound is the result of injury. 
     
     
         18 . A method of treating diabetic retinopathy, comprising:
 administering an antibody which specifically binds to a protein comprising the sequence of SEQ ID NO: 1 to a patient in need thereof, in an amount sufficient to relieve symptoms of diabetic retinopathy.   
     
     
         19 . The method of  claim 18  wherein the antibody is administered directly to the eye. 
     
     
         20 . The method of  claim 18  wherein the antibody is administered systemically. 
     
     
         21 . A method of treating diabetic retinopathy, comprising:
 administering LY294002 to a patient in need thereof, in an amount sufficient to relieve diabetic retinopathy.   
     
     
         22 . The method of  claim 21  wherein the LY294002 is administered directly to the eye of the patient. 
     
     
         23 . The method of  claim 21  wherein the LY294002 is administered systemically. 
     
     
         24 . A method of treating diabetic retinopathy comprising:
 delivering to a patient with diabetic retinopathy an antisense construct comprising at least 15 nucleotides of a human HIMF cDNA, whereby cell of the patient's retina express an mRNA molecule which is complementary to native HIMF mRNA.   
     
     
         25 . A method of treating diabetic retinopathy comprising:
 delivering to a patient with diabetic retinopathy an RNA interference construct comprising at least 19 nucleotides of a human HIMF cDNA, whereby cells of the patient's retina express a double stranded RNA molecule one of whose strands is complementary to native HIMF mRNA.   
     
     
         26 . A method of treating diabetic retinopathy comprising:
 delivering to a patient with diabetic retinopathy siRNA comprising 19 to 21 bp duplexes of a human HIMF mRNA with 2 nt 3′ overhangs, whereby HIMF mRNA produced by the patient's retina cells is cleaved.   
     
     
         27 . A method of treating diabetic retinopathy comprising:
 delivering to a patient with diabetic retinopathy an antisense oligonucleotide comprising at least 15 nucleotides of a human HIMF cDNA, whereby cells of the patient's retina express an mRNA molecule which is complementary to native HIMF mRNA.