Angiotensin-Converting Enzyme Inhibitor Enalapril Reduces Formation of Hypertrophic Scars in a Rabbit Ear Wounding Model

Uzun, Hakan; Bitik, Ozan; Hekimoğlu, Rümeysa; Atilla, Pergin; Kaykçoğlu, Aycan Uğur

doi:10.1097/prs.0b013e31829acf0a

Cited by 38 publications

(30 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent studies have shown that AngII plays an important role in dermal scarring [14, 15, 18]. As reported by Morihara et al , there is increased expression of ACE by human keloid and HSc fibroblasts as compared to unwounded fibroblasts [14].…”

Section: Discussionmentioning

confidence: 99%

“…Alternative HSc models could further validate the results. In a model of HSc using a rabbit ear model, Uzun et al found that animals treated with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had decreased fibroblast density, capillary density, and scar elevation, as compared to groups treated with intra-lesion steroids – the current standard of care treatment for HSc [15]. The authors hypothesized that the mechanism through which enalapril diminished hypertrophic scarring was prevention of AngII-AT1-receptor stimulation of TGFβ.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Ehanire

Ren

Bond³

et al. 2014

J Mol Med

View full text Add to dashboard Cite

Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility are key to mitigating HSc. AngiotensinII (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors AT1-receptor and AT2-receptor, and analyzed for AT1-receptor expression using western blot. In-vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1-receptor, AT2-receptor, p38, JNK, MEK, and ALK5 antagonism. Excisional wounds were created on AT1-receptor KO and WT mice treated with AngII ± Losartan, and ALK5 and JNK inhibitors SB-431542 and SP-600125 respectively. Granulation tissue contraction was quantified and wounds analyzed by immunohistochemistry. AT1-receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1-receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In-vivo experiments determined that absence of AT1-receptor and chemical AT1-receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII, promotes granulation tissue contraction through AT1-receptor and downstream canonical TGFβ signaling pathway; ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Ehanire

Ren

Bond³

et al. 2014

J Mol Med

View full text Add to dashboard Cite

show abstract

“…Human scarring has unique features; thus, animal models for the development of new therapeutic interventions are limited. Scientists have used a rabbit ear wound model (13) or a murine scar model (23) in their studies. Despite some differences between murine and human wound healing (24), similar to human wound healing by secondary intention, these wounds heal via myofibroblastdriven contraction, granulation tissue formation, subsequent collagen deposition, and scar formation (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a case report involving 2 patients claimed that lowdose enalapril (an ACEI) improved postsurgical abdominal keloid scarring (12). Hakan et al (13) reported that an early application of enalapril after dermal injury may reduce scar formation in a rabbit ear wound model. These data proved the crucial role of ACE in scar formation, but little attention has been paid to investigating where the ACE is from.…”

mentioning

confidence: 99%

The source of ACE during scar formation is from both bone marrow and skin tissue

et al. 2018

View full text Add to dashboard Cite

Angiotensin-converting enzyme (ACE) has been found in the pathogenesis of various fibrosis diseases, and ACE inhibitor (ACEI) may affect wound healing and cutaneous fibrosis. However, there is no scientific evidence as to where the ACE is produced during scar formation. Whether it is from the cutaneous tissue or the bone marrow, or both remains unknown. In this study, we investigated the source of ACE using bone marrow transplantation in genetically modified mice, analyzed the inflammatory milieu and some growth factors in the middle of the wound healing period (4 d after the wound was induced). After having deleted the ACE from bone marrow or skin tissue, the wound/scar width in the low-ACE groups were narrower than those in wild-type (WT) controls. Loosely arranged collagen deposition and reduced vessel density were also detected in ACE-deficient mice. Lower ACE levels during scar formation were also accompanied by lower levels of TGF-β1. In the middle of the wound healing period, ACE levels affected the inflammatory cells significantly. In the mice with a deficiency in ACE, the expression of TGF-β1 and TNF-α decreased, but not that of IL-4. Our findings indicate that both bone marrow and skin tissue release ACE during scar formation. Deleting either of them can affect the inflammatory cells and growth factors and reduce the expression of TGF-β1, resulting in a decreased level of scarring.-Fang, Q.-Q., Wang, X.-F., Zhao, W.-Y., Chen, C.-Y., Zhang, M.-X., Shi, B.-H., Zhang, L.-Y., Tan, W.-Q. The source of ACE during scar formation is from both bone marrow and skin tissue.

show abstract

“…Hypertrophic scarring is a common proliferative disorder of dermal fibroblasts characterized by collagen overproduction and excessive deposition of extracellular matrix and occurs in healing wounds elicited by trauma, inflammatory reactions, and deep burn [1,2]. As a result of aberrant wound healing, hypertrophic scar is characterized by a raised, rigid and red appearance associated with pain and itch [3].…”

Section: Introductionmentioning

confidence: 99%

Compound Astragalus and Salvia miltiorrhiza Extract Suppresses Rabbits' Hypertrophic Scar by Modulating the TGF-β/Smad Signal

Jiang²,

Boye³

et al. 2014

Dermatology

View full text Add to dashboard Cite

Background: Hypertrophic scar is a fibro-proliferative disease. Our previous studies demonstrate that compound Astragalus and Salvia miltiorrhiza extract (CASE) inhibits proliferation and invasion in keloid fibroblasts. Objective: To investigate the effects of CASE on hypertrophic scar. Methods: Rabbits were divided into the control, model and three dosage groups of CASE (0.94, 1.88, 3.76%). An animal model of hypertrophic scar was established and treated with CASE ointment or ointment base. The histopathological detection by hematoxylin & eosin and Masson's trichrome staining and protein expression of scars by Western blot were performed. Results: The hydroxyproline content was decreased under CASE treatment. Transforming growth factor beta 1 (TGF-β₁) protein expression increased in the model group while it decreased under CASE treatment. The elevated expression of Smad4 protein was decreased under CASE treatment. Additionally, CASE promoted Smad7 protein expression. Conclusion: CASE could inhibit formation of hypertrophic scar by modulating TGF-β/Smad signal and may be useful for the treatment of hyperplastic scars.

show abstract

Angiotensin-Converting Enzyme Inhibitor Enalapril Reduces Formation of Hypertrophic Scars in a Rabbit Ear Wounding Model

Abstract: Early application of enalapril following dermal injury reduces formation of hypertrophic scars, probably because of its down-regulatory effects on type III collagen production.

Cited by 38 publications

References 36 publications

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

The source of ACE during scar formation is from both bone marrow and skin tissue

Compound <b><i>Astragalus</i></b> and <b><i>Salvia miltiorrhiza</i></b> Extract Suppresses Rabbits' Hypertrophic Scar by Modulating the TGF-β/Smad Signal

Contact Info

Product

Resources

About