Acceleration of Healing, Reduction of Fibrotic Scar, and Normalization of Tissue Architecture by an Angiotensin Analogue, NorLeu3-A(1-7)

Abstract

Angiotensin peptides have been demonstrated to modulate cellular proliferation, angiogenesis, and dermal repair. In this report, the effects of an analogue of the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7) (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models were used to evaluate the normal (rats) and delayed (diabetic mice) healing responses of full-thickness excision wounds and the healing responses of full-thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil, Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor used clinically for the treatment of diabetic ulcers) in accelerating tissue repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and Regranex were statistically significant (n = 5 per group). Full healing was observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1-7) by day 18 after injury, at which time full healing of wounds on placebo-treated or Regranex-treated diabetic mice was not observed. In the rat incision model, accelerated healing and reduced gross appearance of scarification were observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the healing wounds. This action was more pronounced with longer administration of the peptide after injury. In fact, if systemic administration of the peptide (NorLeu3-A(1-7)) was continued during the remodeling phase, then the formation of new adnexal structures at the center of full-thickness excision wounds was observed, with an increase in the appearance of small immature hair follicles at the sites of the excision wounds. The action of this peptide was blocked by the AT receptor antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that this novel angiotensin peptide has the potential to be of benefit in accelerating wound repair and reducing scar formation.

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

“…Exogenous administration of up to 100 μg Ang II per day improved diabetic wound healing in mice, and the Ang II analog (1-7) also improved wound healing (23,24). In addition, studies have also demonstrated increased endogenous levels of Ang II, ACE activity and angiotensin receptors in dermal wound repair (39,40).…”

“…Immunohistochemical staining of normal skin, wounded skin and hypertrophic scars has revealed that AT 1 and AT 2 expression are increased in scar epithelium and endothelium and that angiotensin-converting enzymes (ACE) activity is also increased, but reports of these findings do not describe immunostaining of the deep dermis (15,16). Administration of Ang II and its nonhypertensive analog angiotensin (1-7) accelerates dermal repair in rodents (23,24). The role of Ang II signaling in keloid pathogenesis is unknown.…”

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…14 However, research involving Ang-(1-7) is not restricted to cardiovascular and renal function. In recent years, investigations have demonstrated Ang-(1-7)-dependent effects on wound healing, 15 mechanisms involved in learning and memory, 16 cancer [17][18][19] and early progenitor cells. 20 Previously, we have shown that the receptor Mas is associated with Ang-(1-7)-stimulated intracellular signaling.…”

Development of angiotensin II (1-7) analog as an oral therapeutic for the treatment of chemotherapy-induced myelosuppression

“…9 Though A(1-7) has a well-documented ability to treat chemotherapy-induced myelosuppression, thus far, the development of Nle 3 -A(1-7) focused on its use as topical agent for healing dermal injuries. 6,[8][9][10] Therefore, in our understanding, this is the first study of Nle 3 -A(1-7) in this setting. Finally, in contrast to Nle 3 -A(1-7), treatment with the ARB losartan had no progenitor effect, further supporting the functional differences between A-II blockers and Mas agonists.…”

“…In a number of studies, Nle 3 -A(1-7) displayed a greater ability to stimulate wound healing than A(1-7). 10 While clinical data supports the potential of peptide Mas agonists to stimulate hematopoietic recovery, we sought to develop novel formulations that allow for oral administration of A(1-7) and Nle 3 -A(1-7).…”