Cardioprotective role of hepatic cells and hepatocyte secretory factors in myocardial ischemia
The present invention provides methods, compositions, and systems for treating a subject at risk for, with, or suspected of having, myocardial ischemia using hepatocyte secretory factors (e.g., AGP2, BMPER, FGF21, NRG4, and/or TFF3) or using factors that promote liver cell migration to ischemic myocardial tissue (e.g., IL-6 and/or MMP-2).
1. A method of treating a subject having myocardial ischemia comprising: administering a composition to a subject having myocardial ischemia such that myocardial injury in said subject is reduced, wherein said composition comprises at least one factor selected from the group consisting of:
i) α-1-acid glycoprotein 2 (AGP2) or a biologically active fragment thereof;
ii) bone morphogenetic protein binding endothelial regulatory (BMPER) or a biologically active fragment thereof and
iii) trefoil factor 3 (TFF3) or a biologically active fragment thereof.
2. The method of claim 1 , wherein said at least one factor is α-1-acid glycoprotein 2 (AGP2) or a biologically active fragment thereof.
3. The method of claim 1 , wherein said at least one factor is administered at a dosage of 5 μg/kg-75 μg/kg.
4. The method of claim 1 , wherein said at least one factor is administered at a dosage of 15 μg/kg-50 μg/kg.
5. The method of claim 4 , wherein said BMPER is administered at a dosage of 15 μg/kg-35 μg/kg.
6. The method of claim 1 , wherein said at least one factor comprises at least two of said factors.
7. The method of claim 1 , wherein said at least one factor is bone morphogenetic protein binding endothelial regulator (BMPER) or a biologically active fragment thereof.
8. The method of claim 1 , wherein said at least one factor comprises trefoil factor 3 (TFF3) or a biologically active fragment thereof.
9. The method of claim 1 , wherein said administration is performed intravenously.
10. A method of treating a human subject having myocardial ischemia comprising: administering a composition to a human subject having myocardial ischemia such that myocardial injury in said subject is reduced, wherein said composition comprises at least one factor selected from the group consisting of:
i) α-1-acid glycoprotein 2 (AGP2) as shown in SEQ ID NO: 11, or a biologically active variant or biologically active fragment of SEQ ID NO:11 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:11;
ii) bone morphogenetic protein binding endothelial regulatory (BMPER) as shown in SEQ ID NO:13, or a biologically active variant or biologically active fragment of SEQ ID NO:13 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:13; and
iii) trefoil factor 3 (TFF3) as shown in SEQ ID NO:25, or a biologically active variant or biologically active fragment of SEQ ID NO:25 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:25.
11. The method of claim 10 , wherein said at least one factor comprises a biologically active variant of SEQ ID NO:11 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:11.
12. The method of claim 10 , wherein said at least one factor comprises a biologically active variant of SEQ ID NO:13 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:13.
13. The method of claim 10 , wherein said at least one factor comprises a biologically active variant of SEQ ID NO:25 that has one or two amino acid changes from the corresponding sequence in SEQ ID NO:25.