Novel, protective, anti-inflammatory receptor and its use in preservation of mitochondrial function, wound healing and repair

Abstract

Provided herein is a novel mitochondrial Angiotensin II type 1 and type 2 AT 1 R and AT 2 R receptor which plays a role in protection of mitochondria against oxidative damage. Evidence from animal studies indicates a role for this receptor in preservation of mitochondria and up-regulation of survival genes, anti-inflammatory action, and improvement of wound healing in the skin and soft tissues. Pharmaceutical compositions for treatment directed to preserving mitochondrial function, anti-inflammation, wound healing and decreasing the signs of aging, as well as medicaments and their use are also provided.

1 . A topical dermal pharmaceutical composition comprising at least one angiotensin II type 1 receptor (AT 1 R) antagonist, or a salt, solvate, or derivative, or isoforms thereof, and a pharmaceutically acceptable carrier. 
     
     
         2 . (canceled) 
     
     
         3 . The topical dermal pharmaceutical composition of  claim 1 , further comprising a second active agent. 
     
     
         4 - 15 . (canceled) 
     
     
         16 . A method of identifying candidate ligands that modulate function of AT 2 R that are localized to mitochondria in mammalian cells comprising:
 a) obtaining a sample containing mitochondrial angiotensin type 2 receptors (AT 2 R) in an environment sufficient to maintain physiological function of the AT 2 R,   b) measuring the function of the AT 2 R,   c) contacting the sample with a candidate ligand,   d) measuring the function of the AT 2 R in the presence of the candidate ligand,   wherein a significant difference in the function of the AT 2 R in the presence of the candidate ligand in comparison to function in the absence of the candidate ligand is indicative that the candidate ligand modulates function of mitochondrial AT 2 R.   
     
     
         17 . The method of  claim 16 , wherein the candidate ligand is an agonist of mitochondrial AT 2 R. 
     
     
         18 . The method of  claim 16 , wherein the candidate ligand is an antagonist of mitochondrial AT 2 R. 
     
     
         19 . The method of  claim 16 , wherein the function of mitochondrial AT 2 R is selected from the group consisting of reduction of oxidative damage, preservation of mitochondrial function, maintaining muscle cell function, and upregulation of expression of at least one survival gene. 
     
     
         20 . A method for modulating aging processes in a mammalian cell by reducing the activity of angiotensin type 1 receptors (AT 1 R) comprising contacting a mammalian cell comprising mitochondria expressing both AT 2 R and AT 1 R with a compound that increases the activity of the AT 2 R, wherein an increase in the activity of the AT 2 R reduces the activity of the AT 2 R in the cell and modulates cellular aging processes. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The method of  claim 20 , wherein alteration of cellular aging is selected from the group consisting of: vasodilatation, growth, differentiation, reduced inflammatory signaling cascades, production of nitric oxide, inhibition of fibroblast proliferation, and modulation of apoptosis. 
     
     
         24 . The method of  claim 20 , wherein alteration of cellular aging is selected from the group consisting of: vasoconstriction, reduction of growth, proliferation, increased inflammatory signaling cascades, production of O 2 , stimulation of fibroblast proliferation, and modulation of apoptosis. 
     
     
         25 . The method of  claim 20 , wherein the cells that express mitochondrial AT 2 R are selected from the group consisting of: skeletal muscle cells, monocytes, kidney cells and heart cells. 
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method of  claim 16 , wherein the candidate ligand is selected from the group consisting of CGP42112A and PD123319. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method for treating a skin lesion or wound in a mammal comprising applying a therapeutically effective amount of a topical dermal pharmaceutical composition comprising at least one angiotensin II type 1 receptor (AT 1 R) antagonist, or a salt, solvate, or derivative, or isoforms thereof, and a pharmaceutically acceptable carrier. 
     
     
         34 . The method of  claim 33 , wherein the topical dermal pharmaceutical composition further comprises a second active agent. 
     
     
         35 . The method of  claim 33 , wherein the composition is applied topically at injured, inflamed, scarred or damaged skin, subcutaneous or skeletal muscle areas. 
     
     
         36 . The method of  claim 33 , wherein the wound or skin lesion is acne. 
     
     
         37 . The method of  claim 33 , wherein the wound or skin lesion was due to a burn or thermal injury. 
     
     
         38 . The method of  claim 33 , wherein the wound or skin lesion was due to aging. 
     
     
         39 . The method of  claim 33 , wherein the wound or skin lesion was due to diabetes.