Modulation of nitric oxide synthase by PKC

• US 20020048581A1
• Filed: 07/17/2001
• Published: 04/25/2002
• Est. Priority Date: 07/18/2000
• Status: Abandoned Application

• Current Assignee: Joslin Diabetes Center Inc.
• Original Assignee: Joslin Diabetes Center Inc.
• Inventors: King, George L.
• Application Number:
  US09/907,012
• Publication Number:
  US 20020048581A1
• Time in Patent Office: Days
• US Class Current: 424/146.1
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes

Abstract

Featured are methods of modulating endothelial NOS (eNOS) expression, e.g., insulin-stimulated eNOS expression, by modulating PKCβ. The methods are useful in the treatment of insulin-related disorders, e.g., hypertension.

Claims

1. A method of modulating endothelial cell nitric oxide synthase (eNOS) in a cell, tissue, or subject, comprising modulating a PKC β

.

2. The method of claim 1, wherein the PKCβ

is PKCβ

1.

3. The method of claim 1, wherein modulating a PKC β

comprises administering to the cell, tissue, or subject an inhibitor of PKC β

.

4. The method of claim 3, wherein the inhibitor of PKC β

is LY333531.

5. The method of claim 3, wherein the inhibitor of PKCβ

is selected from the group of;

an inhibitory PKCβ

antibody, a PKCβ

antisense nucleic acid, an inhibitory PKCβ

binding peptide, and an inhibitory PKCβ

binding small molecule.

6. The method of claim 3, wherein the subject exhibits an insulin related disorder.

7. The method of claim 6, wherein the insulin related disorder is insulin resistance;

diabetes, atherosclerosis, or hypertension.

8. The method of claim 1, wherein modulating a PKC β

comprises administering to the cell, tissue, or subject a PKC β

agonist.

9. The method of claim 8, wherein the PKC β

agonist is selected from the group of;

PKCβ

polypeptide or functional fragment or analog thereof;

a nucleic acid sequence encoding a PKCβ

polypeptide or a functional fragment or analog thereof; and

an agent which increases PKCβ

expression.

10. A method of increasing eNOS in a cell, tissue, or subject, comprising inhibiting a PKCβ

.

11. The method of claim 10, wherein inhibiting a PKCβ

comprises administering to the cell, tissue, or subject a PKCβ

inhibitor.

12. The method of claim 10, wherein the inhibitor of PKCβ

is selected from the group of;

an inhibitory PKCβ

antibody, a PKCβ

antisense nucleic acid, an inhibitory PKCβ

binding peptide, and an inhibitory PKCβ

binding small molecule.

13. The method of claim 11, wherein the PKCβ

inhibitor is LY333531.

14. The method of claim 10, wherein eNOS mRNA levels are increased.

15. The method of claim 10, wherein the subject has an insulin related disorder.

16. The method of claim 15, wherein the insulin related disorder is hypertension.

17. The method of claim 15, wherein the insulin related disorder is diabetes.

18. The method of claim 15, wherein the insulin related disorder is atherosclerosis.

19. The method of claim 15, wherein the insulin related disorder is insulin resistance.

20. A method of increasing eNOS in a cell, tissue, or subject, comprising increasing a PI3 kinase activity.

21. The method of claim 20, wherein eNOS mRNA levels are increased.

22. The method of claim 20, wherein the subject has an insulin related disorder.

23. The method of claim 22, wherein the insulin related disorder is hypertension, diabetes, atherosclerosis, ischemia, or insulin resistance.

26. The method of claim 25, wherein the control is a non-hypertensive subject, or a cell or tissue therefrom.

24. A method of treating hypertension in a subject, comprising:

identifying a subject in need of treatment for hypertension; and

administering LY333531, wherein LY333531 increases eNOS expression in a tissue of the subject.

25. A method of determining if a subject is at risk for hypertension, comprising:

evaluating a PKCβ

activity in a cell or tissue of the subject,

comparing the PKCβ

activity in the cell or tissue of the subject to a control.