Hypoxia induced mitogenic factor
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-1 or angiotensin II.
1. A method of treating hypertrophic cardiomyopathy by inhibiting expression of HIMF, comprising:
delivering to a heart cell of a patient with hypertrophic cardiomyopathy an antisense construct comprising at least 15 nucleotides of a human hypoxia induced mitogenic factor (HIMF) cDNA, whereby the heart cell expresses an mRNA molecule which is complementary to native HIMF mRNA, thereby inhibiting expression of HIMF.
2. A method of treating hypertrophic cardiomyopathy by inhibiting expression of HIMF, comprising:
delivering to a heart cell of a patient with hypertrophic cardiomyopathy an RNA interference construct comprising at least 19 nucleotides of a human hypoxia induced mitogenic factor (HIMF) cDNA, whereby the heart cell expresses a double stranded RNA molecule one of whose strands is complementary to native HIMF mRNA, thereby inhibiting expression of HIMF.
3. A method of treating hypertrophic cardiomyopathy by inhibiting expression of HIMF, comprising:
delivering to a heart cell of a patient with hypertrophic cardiomyopathy siRNA comprising 19 to 21 bp duplexes of a human hypoxia induced mitogenic factor (HIMF) mRNA with 2 nt 3′ overhangs, whereby HIMF mRNA produced by the heart cell is cleaved, thereby inhibiting expression of HIMF.
4. A method of treating hypertrophic cardiomyopathy by inhibiting expression of HIMF, comprising:
delivering to a heart cell of a patient with hypertrophic cardiomyopathy an antisense oligonucleotide comprising at least 15 nucleotides of a human hypoxia induced mitogenic factor (HIMF) cDNA, whereby the heart cell expresses an mRNA molecule which is complementary to native HIMF mRNA, thereby inhibiting expression of HIMF.