138 Modulation of Gene Expression by Norleu 3 A(1–7) in Diabetic Wounds

Neuropathic ulcers represent a significant cause of morbitity for diabetics in the United States. Diabetic wounds are notoriously difficult to resolve. Treatment options are limited due in part to the lack of knowledge about the molecular events that regulate successful resolution of wounds. To identify differences between normal and diabetic gene regulation in wounds, we examined the level of expression of 12,000 genes in granulation tissue and wound‐edge epithelium in normal animals and in an experimental model of diabetes following induction of full thickness skin injuries. Full thickness injuries in diabetic mice were characterized in part by altered regulation of structural genes and genes that regulate energy metabolism and utilization. The energy cycle contributes backbone structures for the synthesis of a variety of amino acids, the molecular building blocks essential for wound repair. A direct consequence of a diminished ability to efficiently exploit energy supplies would be decreased availability of regulatory and structural proteins necessary for efficient healing in diabetic wounds. We have successfully enhanced healing in diabetic wounds by treatment with the angiotensin II peptide NorLeu3A(1–7). NorLeu3A(1–7) accelerates healing of full thickness injuries in diabetic mice. While NorLeu3A(1–7) enhances healing by accelerating collagen deposition and reepithelialization, gene array studies show that NorLeu3A(1–7) acts locally within the wound site by altering gene expression within the granulation tissue. Specifically at day 7 after injury, NorLeu3A(1–7) reduced the expression of MMP genes and increase the expression of genes involved in energy metabolism. Supported by PHS grant NIAMS 2 R44 AR47481