Compositions and methods of using micro RNAs
The present invention provides compositions and methods of using microRNAs to treat pulmonary arterial hypertension. In one aspect, methods are disclosed that are useful for identifying a subject in need of therapeutic intervention to reduce or improve a symptom of pulmonary arterial hypertension, reducing proliferation of pulmonary vascular cells in a subject, or treating pulmonary arterial hypertension in a subject. In another aspect, compositions include an inhibitor of fibroblast growth factor 2 (FGF2) expression comprising at least one of: a mature sequence of miR-424 or miR-503; a pri-miRNA of miR-424 or miR-503; a pre-miRNA of miR-424 or miR-503; and the complement thereof. Pharmaceutical compositions for reducing proliferation of pulmonary vascular cells in a subject in need thereof and biomarker panels are also disclosed.
1. A composition comprising an effective amount of an inhibitor of fibroblast growth factor 2 (FGF2) expression comprising at least one of: a mature sequence of miR-424 and miR-503; a pri-miRNA of miR-424 and miR-503; a pre-miRNA of miR-424 and miR-503; and the complement thereof, wherein the composition is formulated for delivery to a pulmonary endothelial cell and wherein the composition reduces proliferation of the pulmonary endothelial cell.
2. The composition of claim 1 , wherein the mature sequence comprises a polynucleotide selected from the group consisting of: a nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; a nucleotide sequence consisting of 30 to 120 nucleotides which has an identity of at least 85% to the nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; or the complement thereof.
3. The composition of claim 1 , wherein the inhibitor is expressed by a recombinant expression vector.
4. A pharmaceutical composition for reducing proliferation of pulmonary vascular cells in a subject in need thereof comprising the composition of claim 1 and a pharmaceutically acceptable carrier.
5. A method of reducing proliferation of pulmonary vascular cells in a subject in need thereof comprising administering to the pulmonary vascular cells of the subject the composition of claim 1 , wherein the proliferation of pulmonary vascular cells is reduced in the subject following administration of the composition.
6. The method of claim 5 , wherein the mature sequence comprises a polynucleotide selected from the group consisting of: a nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; a nucleotide sequence consisting of 30 to 120 nucleotides which has an identity of at least 85% to the nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; or the complement thereof, wherein the pulmonary arterial hypertension is reduced in the subject following administration of the composition.
7. A method of treating pulmonary arterial hypertension in a subject in need thereof comprising administering to the pulmonary vascular cells of the subject the composition of claim 1 , wherein the pulmonary arterial hypertension is reduced in the subject following administration of the inhibitor.
8. The method of claim 7 , wherein the mature sequence comprises a polynucleotide selected from the group consisting of: a nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; a nucleotide sequence consisting of 30 to 120 nucleotides which has an identity of at least 85% to the nucleotide sequence as shown in SEQ ID NO: 9 or SEQ ID NO: 10; or the complement thereof.
9. The method of claim 7 , wherein the step of administering the inhibitor further comprises administering a recombinant expression vector comprising the inhibitor.