Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

https://doi.org/10.1016/j.bbrc.2013.10.162Get rights and content

Highlights

  • •

    Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin.

  • •

    Administration of an ACE inhibitor improved UVB-induced skin wrinkle.

  • •

    ACE inhibitor improved UVB-induced epidermal hypertrophy.

  • •

    ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin.

Abstract

Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

Introduction

Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II, an octapeptide that is a major effector of the rennin-angiotensin blood pressure regulation system. Angiotensin II signaling is also known to play important roles in regulation of cell proliferation, differentiation, apoptosis and tissue remodeling, and two types of angiotensin II receptors, AT1 and AT2, are expressed in mammalian cells.

In skin, angiotensin II signaling is involved in wound healing, fibrosis, hypertrophic scar formation and inflammatory responses [1], [2], [3], [4], [5]. Angiotensinogen, ACE, and angiotensin II receptors are expressed in skin [6], and keratinocytes and fibroblasts in wounded skin express high levels of angiotensin II receptors [1]. As regards the molecular mechanism through which angiotensin II contributes to wound healing, it has been reported that angiotensin II promotes re-epithelization through formation of reactive oxygen species (ROS) and induction of epidermal growth factor (EGF) receptor expression in epidermis [2], [3], [7], and also stimulates synthesis of extracellular matrix components via TGF-β signaling in dermis [8]. Moreover, ACE expression is higher in pathologic scars than in normal or wounded skin [4]. Over-expression of ACE and high levels of angiotensin II signaling also participate in inflammation and fibrosis associoated with pathologic scar formation [2], [3], [5], [8]. It was reported that exogenous angiotensin II induced differentiation of fibroblasts to myofibroblasts and migration of inflammatory cells via increased expression of pro-inflammatory chemokines in mouse skin [5].

UVB is thought to be a major contributor to photoaging [9]. UVB damages skin cells and tissues both directly and indirectly through inflammation and production of reactive oxygen species [10], [11]. In epidermis, increased expression of epidermal growth factor receptor (EGFR) induced by UVB via ROS synthesis causes epidermal hyperplasia and keratosis [12], [13]. In dermis, on the other hand, UVB induces an imbalance of production and degradation of extracellular matrix (ECM) components and damages the ECM, causing loss of skin elasticity and wrinkle formation [14], [15], [16], [17]. Exogenous matrix metalloproteinase (MMP) inhibitors or endogenous tissue inhibitor of MMPs (TIMPs) have a protective effect against UVB-induced wrinkle formation [18], [19]. The skin of hairless mice repeatedly exposed to UVB has been used as a model of photoaged skin for investigating mechanisms of UVB-induced wrinkle formation and repair [18], and the mechanism of wrinkle repair, as well as the effects of retinoids on it, have been studied using this animal model [20], [21].

Skin responses to UVB irradiation and photoaging processes exhibit similarities to the processes of wound healing and inflammation, which involve angiotensin II signaling. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the participation of ACE activity and angiotensin II signaling in skin photoaging in a UVB-irradiated hairless mouse model, and investigated the effect of an ACE inhibitor, enalapril maleate.

Section snippets

Reagent

Enalapril maleate was purchased by Wako Pure Chemical Industries, Ltd. (Osaka, Japan).

Animals

Male hairless mice of the SKH-1 strain were purchased from Charles River Laboratories Japan, Inc. (Tokyo, Japan). These animals were approximately 6 weeks old at the start of the experiment. They were fed water and a commercial diet (CRF-1, Oriental Yeast Co., Ltd, Tokyo, Japan) ad. libitum. All experimental procedures using mice were approved by the Animal Experiment Committee of Tokyo University of

UVB induces angiotensin II signaling in epidermis of mouse skin

In hairless mouse skin before UVB treatment, angiotensin II was not detectable (Fig. 1A), though strong staining for ACE was detected in epidermal cells and dermal cells (Fig. 1B). The AT1 receptor was distributed in some dermal cells and epidermal basal cells (Fig. 1C), while AT2 receptor was expressed only in some dermal cells (Fig. 1D). After 8-week UVB irradiation, the skin exhibited marked epidermal hyperplasia (Fig. 1E–H). Angiotensin II expression was induced in the epidermis (Fig. 1E),

Discussion

Expression and activity of ACE are enhanced in wounded skin, and are necessary for wound healing [2]. However, overexpression of ACE and increased angiotensin II signaling induce inflammatory responses that lead to pathological scar formation and fibrosis [1], [4], [5]. It is well known that UVB induces inflammation and various disorders in the skin [18], [26], [27], including epidermal hyperplasia, dysfunction of basement membrane, and degradation of ECM in the dermis [18]. These changes are

References (42)

  • G. Imokawa

    Mechanism of UVB-induced wrinkling of the skin: paracrine cytokine linkage between keratinocytes and fibroblasts leading to the stimulation of elastase

    J. Invest. Dermatol. Symp. Proc.

    (2009)
  • S. Inomata et al.

    Possible involvement of gelatinases in basement membrane damage and wrinkle formation in chronically ultraviolet B-exposed hairless mouse

    J. Invest. Dermatol.

    (2003)
  • U. Yokose et al.

    The endogenous protease inhibitor TIMP-1 mediates protection and recovery from cutaneous photodamage

    J. Invest. Dermatol.

    (2012)
  • S. Chen et al.

    Effects of all-trans retinoic acid on UVB-irradiated and non-irradiated hairless mouse skin

    J. Invest. Dermatol.

    (1992)
  • M. Naganumaa et al.

    Delayed induction of pigmented spots on UVB-irradiated hairless mice

    J. Dermatol. Sci.

    (2001)
  • M.F. Bennett et al.

    Skin immune systems and inflammation: protector of the skin or promoter of aging?

    J. Invest. Dermatol. Symp. Proc.

    (2008)
  • H.W. Liu et al.

    Angiotensin II regulates phosphoinositide 3 kinase/Akt cascade via a negative crosstalk between AT1 and AT2 receptors in skin fibroblasts of human hypertrophic scars

    Life Sci.

    (2006)
  • D.A. Lewis et al.

    UVB-induced activation of NF-kappaB is regulated by the IGF-1R and dependent on p38 MAPK

    J. Invest. Dermatol.

    (2008)
  • R.S. Meyers et al.

    Pharmacotherapy review of chronic pediatric hypertension

    Clin. Ther.

    (2011)
  • U.M. Steckelings et al.

    Differential expression of angiotensin receptors in human cutaneous wound healing

    Br. J. Dermatol.

    (2005)
  • L. Stawski et al.

    Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis

    Arthritis Res. Ther.

    (2012)

    • Cited by (14)

    • Critical role of the endogenous renin-angiotensin system in maintaining self-renewal and regeneration potential of epidermal stem cells

      2019, Biochimica et Biophysica Acta - Molecular Basis of Disease
      Citation Excerpt :

      Ang II is the main effector molecule of the RAS, deriving from angiotensinogen by successive enzymatic actions of renin and ACE. Mounting evidence demonstrated that tightly controlled RAS activity is critical not only for maintaining systemic hemodynamics and blood volume but also for controlling cell proliferation, differentiation, and tissue remodeling in target organs [1]. Chronic RAS activation in the cardiovascular system increases Ang II and plays a major role in the pathogenesis of cardiovascular diseases such as hypertension and heart failure [2].

    • Balance and circumstance: The renin angiotensin system in wound healing and fibrosis

      2018, Cellular Signalling
      Citation Excerpt :

      Photoaging of the skin elevates the levels of ACE and Ang II. Interestingly, it also enhances AT1 in the epidermis and AT2 in the dermis, suggesting elevated AT1 signaling in the epidermis and elevated AT2 signaling in the dermis of photoaged skin [66]. The changes observed in the AT1:AT2 ratio in diabetes and during natural and photo-induced aging may be one contributing factor that predisposes such individuals to developing a wound healing pathology.

    • Aliskiren: Preclinical evidence for the treatment of hyperproliferative skin disorders

      2018, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      In the present study, inhibition of renin promoted a reduction in epidermal hyperproliferation, as observed by epidermis thickness and PCNA expression. Similar results were observed by Matsuura-Hachiya et al., who showed that enalapril maleate, an inhibitor of angiotensin-converting enzyme, reduced epidermal hyperplasia induced by UVB irradiation [24]. Psoriasis is characterized by epidermal hyperproliferation, a result of hyperproliferative and undifferentiated keratinocytes [18].

    • Recovery of extracellular matrix components by enalapril maleate during the repair process of ultraviolet B-induced wrinkles in mouse skin

      2015, Biochemistry and Biophysics Reports
      Citation Excerpt :

      Besides the cardiovascular system, RAS also plays as a local regulator of cell functions and involved in tissue pathologies in many tissues such as skin [13–18]. ACE expression and Ang II levels in hairless mouse skin were enhanced by repeated UVB irradiation, and EM and other ACE inhibitors accelerated recovery of skin from UVB-induced wrinkles [10]. Furthermore, EM treated hairless mouse skin was thinner and showed lower transepidermal water loss (TEWL) than control mice [10].

    • The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases

      2023, Diagnostics

    • Applications of Probiotic Constituents in Cosmetics

      2023, Molecules
    View all citing articles on Scopus
    View full text
    Copyright © 2013 Elsevier Inc. All rights reserved.