GJA1 isoforms protect against metabolic stress
The present invention describes methods of treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a medical condition related to ischemia/reperfusion in a subject using GJA1-20k as a therapeutic agent. The invention further provides a method of protecting a cell from metabolic stress, using GJA1-20k. The invention also provides for a composition and/or gene expression vector comprising GJA1-20k.
1. A method of treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a condition in a subject, comprising: providing a polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or a polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or a gene expression vector comprising a sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, wherein the gene expression vector is configured for expressing the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3; and administering a therapeutically effective amount of the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, the polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, to the subject, thereby treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of the condition in the subject, wherein the condition is metabolic stress, ischemia, or both.
2. The method of claim 1 , wherein the subject is one who has had a previous myocardial infarction.
3. The method of claim 1 , wherein the administration of the polypeptide consisting of the GJA1-20k polypeptide or the GJA1-20k polypeptide fused to the CPP results in a cardioprotective effect.
4. The method of claim 3 , wherein the cardioprotective effect comprises a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.
5. The method of claim 1 , wherein the administration of the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide results in a cardioprotective effect.
6. The method of claim 5 , wherein the cardioprotective effect comprises a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.
7. A method of protecting a cell from metabolic stress, comprising:
providing
a polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or
a polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or
a gene expression vector comprising a sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, wherein the gene expression vector is configured for expressing the GJA1-20k polypeptide having SEQ ID NOs:1, 2 or 3; and contacting the cell with
the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or
polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or
the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, thereby protecting the cell from metabolic stress.
8. The method of claim 7 , wherein contacting the cell with the GJA1-20k polypeptide or the GJA1-20k polypeptide fused to a CPP results in a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.
9. The method of claim 7 , wherein contacting the cell with the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 results in a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.
10. The method of claim 1 , wherein the subject has or is having a myocardial infarction, open heart surgery, cardiopulmonary bypass, coronary artery reperfusion, stroke, ischemic stroke, or nephrotoxicity.
11. The method of claim 1 , wherein treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of metabolic stress or ischemia results in treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of reperfusion injury in a subject who underwent or is undergoing reperfusion.
12. The method of claim 1 , wherein the polypeptide consisting of the GJA1-20k polypeptide, polypeptide consisting of the GJA1-20k polypeptide fused to the CPP, or the gene expression vector is provided in a composition.
13. The method of claim 7 , wherein the polypeptide consisting of the GJA1-20k polypeptide, polypeptide consisting of the GJA1-20k polypeptide fused to the CPP, or the gene expression vector is provided in a composition.