Article pubs.acs.org/jnp
Upregulation of Collagen Expression via PPARβ/δ Activation in Aged Skin by Magnesium Lithospermate B from Salvia miltiorrhiza Yu Ri Jung,†,‡ Eun Kyeong Lee,†,‡ Dae Hyun Kim,† Chan Hum Park,†,§ Min Hi Park,† Hyoung Oh Jeong,† Takako Yokozawa,⊥ Takashi Tanaka,∥ Dong Soon Im,† Nam Deuk Kim,† Byung Pal Yu,# Sang Hyun Mo,○ and Hae Young Chung*,† †
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea § College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea ⊥ Graduate School of Science and Engineering for Research, University of Toyama, Toyama 930-8555, Japan ∥ Faculty of Pharmaceutical Sciences, Nagasaki University, Nagasaki 852-8131, Japan # Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, United States ○ Bio-FD&C, Incheon 406-840, Republic of Korea ABSTRACT: This study investigated the agonistic activity of magnesium lithospermate B (1), isolated from Salvia miltiorrhiza, on peroxisome proliferator-activated receptor (PPARβ/δ) and the expressions of collagen genes (COL1A1 and COL3A1) and transforming growth factor-β1 (TGF-β1) in models of skin aging. The action of compound 1 as a PPARβ/δ agonist was determined by reporter gene assay, immunostaining, and Western blotting. To determine the antiaging effects of compound 1 on skin, aged Sprague− Dawley rat skin and ultraviolet B (UVB)-irradiated human skin fibroblasts were used. The results show that 1 presented a marked enhancement of both nuclear protein levels and activity of PPARβ/δ in fibroblasts. In addition, 1 prevented downregulation of PPARβ/δ activity in aged rat skin and UVB-induced fibroblasts. Furthermore, 1 increased the expressions of COL1A1, COL3A1, and TGF-β1 in vivo and in a cell culture system. Therefore, the present study shows that compound 1 prevents collagen degradation in aged rat skin and UVB-exposed fibroblasts through PPARβ/δ activation. The therapeutic and cosmetic applications of compound 1 need further investigation.
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TGF-β is a well-known regulator of ECM homeostasis6 and involves UVB-induced reduction of collagen, photoaging, and apoptosis in fibroblast cells.7,8 Also, recent reports show that TGF-β is a molecular target for the peroxisome proliferatoractivated receptor (PPARβ/δ),9 and its upregulation by PPARβ/δ induces the expressions of genes related to ECM regulation. 7 Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily.10 PPARs are attractive targets for the intervention of metabolic diseases as well as the modulation of inflammatory and immune responses. 10 However, recent studies show that PPARs also play an important role in skin homeostasis. Among the three identified PPAR isoforms, PPARβ/δ is ubiquitously expressed in skin cells and is a key mediator of epidermal and dermal aspects of the wound-healing process.11 Recent reports show that
kin aging is the sum of the intrinsic (as a natural consequence of physiological changes) and extrinsic aging processes (from exposure to ultraviolet radiation).1 Features of skin aging include decreased skin elasticity, extracellular matrix (ECM) degradation, and wrinkle formation. Skin aging is characterized by histologic changes, including damage to collagen fibers, excessive deposition of abnormal elastic fibers, and increase of glycosaminoglycans.2 Alterations in collagen, the major structural component of skin, have been suggested as the cause of the clinical changes observed in photoaged and naturally aged skin3 and are mainly affected by two signaling pathways. One major pathway of wrinkle formation is associated with collagen degradation via the upregulation of the expressions of ECM proteases such as activator protein 1 (AP-1) signaling, which induces matrix-metalloproteinases (MMPs).4 Another pathway is related to constitutive attenuation of transforming growth factor-β (TGF-β) and its downstream collagen gene expression.5 © XXXX American Chemical Society and American Society of Pharmacognosy
Received: May 18, 2015
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DOI: 10.1021/acs.jnatprod.5b00348 J. Nat. Prod. XXXX, XXX, XXX−XXX
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PPARβ/δ prevents the degradation of type I (COL1A1) and III (COL13A1) collagen and the secretion of matrix metalloproteinase 1 (MMP1) by inhibiting ROS generation in UVB-induced human skin fibroblasts.12 In addition, PPARβ/δ promotes wound healing through induction of collagens and fibronectin in a TGF-β1-dependent or -independent manner in skin.7 On the basis of these findings, it has been postulated that PPARβ/δ may be a new therapeutic target for the prevention of skin aging. One approach to protect the skin from premature aging and other skin damage is to use active protective agents. In recent years, naturally occurring compounds have gained considerable attention as protective agents against skin damage.13−15 Salvia miltiorrhiza, a medical herb known as danshen, has been used in traditional medicine for the treatment of many diseases such as atherosclerosis, diabetes, and coronary heart disease in many Asian countries, including China, Korea, and Japan.16−18 One of the active components of this herb, magnesium lithospermate B (1), has been reported to have multiple biological functions including antioxidant, neuroprotective, and antidiabetic effects.17−20 Compound 1 ameliorates endothelial dysfunction in diabetes by enhancing vasodilation in addition to reducing oxidative stress21 and attenuates ischemia reperfusion-induced hepatocellular damage by preventing inflammatory responses.22 Also, 1 protects pancreatic β-cells from cytokine-induced apoptosis23 and prevents diabetic atherosclerosis24 by enhancing antioxidant defense mechanisms via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation. Recently, our group reported that compound 1’s anti-inflammatory efficacy was from suppressing nuclear factor kappa B (NF-κB) and AP-1-dependent MMPs by modulating reactive oxygen species (ROS) generation and the mitogen-activated protein kinase (MAPK) signaling pathway in UVB-induced human skin fibroblasts and aged rat skin.13 However, the role of 1 as a potential PPARβ/δ activator preceding the collagen expression in aging was not explored. The current study investigated the effects of 1 on PPARβ/δ activation and the expressions of its target genes TGF-β1, COL1A1, and COL3A1 in aged rat skin and UVB-exposed fibroblasts.
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RESULTS AND DISCUSSION
Activation of PPARβ/δ by Compound 1 in Fibroblasts. PPARs have recently been suggested as pharmacological targets for many skin diseases.25 PPARβ/δ, one of the three PPAR isotypes, has been implicated for its critical role in ECM regulation.25 PPARβ/δ is instrumental in damaged skin repair after injury and has been shown to interact closely with the regulatory elements of collagen genes and to promote wound healing by upregulating the synthesis of ECM proteins, such as type I and III collagen, TGF-β1, and fibronectin.26 These findings imply that PPARβ/δ may be a potential target for skin antiaging intervention. To verify whether 1 induces PPARβ/δ activation, docking simulation, transient transfection, immunostaining, and Western blotting experiments were performed. To identify the effect of 1 as a novel PPARβ/δ agonist, docking simulation experiments were conducted using the Autodock 4.2 program, where 1 linked with 2-bromophenol to provide numerous hydrophobic interactions in the binding pocket. Compound 1 had affinity to the same binding pocket as known PPARβ/δ ligands, GW501516 and GW0742. In addition, the binding energy of 1 (−9.02 kcal/mol) was similar to those of GW501516 (−9.28 kcal/mol) and GW0742 (−9.68 kcal/ mol) (Figure 1A). To confirm the action of 1 on PPARβ/δ DNA binding activity, Hs27 fibroblasts were transiently transfected with PPRE-3X-TK-luc vector and the PPARβ/δ expression vector, followed by the treatment of cells with different doses of 1 or GW501516. Figure 1B shows that the compound 1-treated group has enhanced peroxisome proliferator response elements (PPRE) binding activity compared to that of the non-1-treated group. In particular, the binding activity of compound 1 (10 μM) was greater than that of the positive control, GW501516 (10 μM). Furthermore, immunofluorescence staining revealed that PPARβ/δ was exclusively distributed in the nucleus after treatment with 1 or GW501516 (Figure 1C). 1-treated cells showed greater nuclear translocation of PPARβ/δ compared to that of GW501516-treated cells. The levels of nuclear PPARβ/δ were examined by Western blotting. The data shown in Figure 1D clearly indicate that compound 1 (10 μM) increased the nuclear translocation of PPARβ/δ in fibroblasts compared to that of the non-1treated group. These results support the efficacy of 1 as a PPARβ/δ activator. Enhancement of TGF-β1 and Collagen via PPARβ/δ Activation in the Skin of MLB (1)-Fed Aged Rats. A subsequent question was whether 1 supplementation could reverse the intrinsic aging process. The 20-month-old rat skins were used to evaluate the effect of 1 supplementation on the PPARβ/δ activity and expressions of the ECM-related proteins, TGF-β1 and collagen (COL1A1 and COL3A1). The nuclear level of PPARβ/δ was determined using Western blotting. The results show that the nuclear level of PPARβ/δ decreased in 1untreated old rat skin compared with that of young rat skin. The nuclear level of PPARβ/δ in 1-treated old rat skin increased in a dose-dependent manner compared to that of the 1-untreated old rat skin (Figure 2A). Cytosolic protein levels of TGF-β1, COL1A1, and COL3A1 were lower in 1-treated old rat skin compared to that of young rat skin, whereas these protein levels were significantly higher in 1-untreated old rat skin compared to that of 1-untreated old rat skin (Figure 2B). These results are consistent with the hypothesis that 1 increases B
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Figure 1. Effect of compound 1 on PPARβ/δ activation. (A) Docking simulation was performed to identify interaction between 1 and the ligand binding domain of human PPARβ/δ. Compound 1 has similar binding sites compared with the known PPARβ/δ agonists GW501516 and GW0742. (B) For the luciferase assay, HS27 fibroblasts overexpressing PPARβ/δ were treated with 10 μM compound 1 or 10 μM GW501516 for 6 h. Values are mean ± standard error (SE) of six determinations. Statistical results of one-way analysis of variance (ANOVA): ###p < 0.001 vs pcDNA, *p < 0.05, **p < 0.01 vs PPRE + PPARβ/δ. (C) Cells were treated with 1 or GW501516 for 2 h, fixed, permeabilized, and incubated with rabbit antiPPARβ/δ antibody followed by Cy3-conjugated anti-rabbit IgG (red). The nuclei of the corresponding cells were visualized by Hoechst 33342 staining (blue). Magnification, 400×. (D) Western blotting was performed to detect the levels of PPARβ/δ in fibroblasts. TFIIB was used as nuclear loading control. Statistical results of one-way ANOVA: ***p < 0.001 vs nontreated cells. PPARβ/δ, peroxisome proliferator-activated receptorβ/δ; TFIIB, transcription factor IIB.
Figure 2. Upregulations of PPARβ/δ, TGF-β1, and collagen by compound 1 in aged rat skin. (A and B) Western blotting was performed to detect the nuclear levels of PPARβ/δ and cytosolic levels of TGF-β1, COL1A1, and COL3A1 in aged rat skin. The blots shown are representative of three experiments that yielded similar results. Significance was determined by one-way ANOVA: #p < 0.05, ##p < 0.01 vs young rats; *p < 0.05, **p < 0.01 vs 1-nontreated old rats. COL1A1, alpha-1 type I collagen; COL3A1, alpha-1 type III collagen; TFIIB, transcription factor IIB, TGF-β1, transforming growth factor-β1.
The UVB-exposed fibroblasts were used to test whether 1 could preserve the expression of collagen genes upon UVB exposure through PPARβ/δ activation. First, to verify whether 1 induces the expressions of COL1A1 and COL3A1 via PPARβ/δ, fibroblasts were transfected with a PPARβ/δ siRNA. Compound 1 treatment significantly upregulates the expressions of
TGF-β1 and collagen gene expressions through PPARβ/δ activation in old rat skin. Action Mechanism of MLB (1) for PPARβ/δ Activation and Expressions of TGF-β1 and Collagen Genes in UVBExposed Fibroblasts. The next set of experiments was designed to evaluate the effect of 1 in the photoaging process. C
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Figure 3. Effect of compound 1 on PPARβ/δ-induced TGF-β1 and collagen in UVB-exposed cells. (A) Cells pretreated for 24 h with or without PPARβ/δ siRNA were incubated with 1 (10 μM). (B and C) Cells were pretreated with 1 (2 or 10 μM) for 2 h and then exposed to 30 mJ/cm2 of UVB. After incubation, the levels of PPARβ/δ, TGF-β1, COL1A1, and COL3A1 were determined by Western blotting. TFIIB and β-actin were used as nuclear and cytosol loading controls, respectively. Blots are representative of three experiments that yielded similar results. Significance was determined by one-way ANOVA: ##p < 0.01, ###p < 0.01 vs nontreated cells; **p < 0.01, ***p < 0.001 vs treated cells. COL1A1, alpha-1 type I collagen; COL3A1, alpha-1 type III collagen; TFIIB, transcription factor IIB; TGF-β1, transforming growth factor-β1; UVB, ultraviolet B.
COL1A1 and COL3A1. However, compound 1 treatment on PPARβ/δ siRNA-pretreated cells did not upregulate COL1A1 and COL3A1 (Figure 3A). These results suggest that 1 is involved in the upregulation of type I and III collagen via PPARβ/δ activation. Next, to investigate the effect of 1-induced PPARβ/δ activation in UVB-exposed fibroblasts, the nuclear levels of PPARβ/δ were examined by Western blotting. As shown in Figure 3B, UVB-exposed cells showed decreased nuclear levels of PPARβ/δ compared with those of nonexposed cells. Compound 1 treatment prevented the decrease of PPARβ/δ in a dose-dependent manner in UVB-exposed cells. To gain further insight into the mechanism by which 1 was involved in the PPARβ/δ-mediated expression of collagen genes, we tested the expressions of TGF-β1, COL1A1, and COL3A1 in UVB-exposed fibroblasts. The results of Figure 3C show that the protein levels of TGF-β1, COL1A1, and COL3A1 were decreased by UVB exposure. However, 1 treatment rescued their expression. Therefore, results from this study indicate that 1 increases the expressions of the ECMrelated genes, TGF-β1 and type I and III collagen, through PPARβ/δ activation. Thus, 1 might boost collagen production during skin aging (Figure 4). The regulation of collagen expression involves complex signaling as shown by Ham et al.,7 who demonstrated that PPARβ/δ activation induced collagen expression by directly binding to the type III collagen promoter or by indirectly upregulating the TGF-β1 signaling pathway in skin tissue. TGF-β1 is the major regulator of type I pro-collagen synthesis, and it plays a role in downregulating proteolytic enzymes such as collagenase in human skin connective tissue.27 TGF-β1 binds
Figure 4. Possible mechanism of collagen synthesis by compound 1 in aging skin. Magnesium lithospermate B (1) binds PPARβ/δ, and the activated PPARβ/δ promotes the expressions of ECM-related genes including TGF-β1, COL1A1, and COL3A1, preventing collagen degradation in the skin aging process.
to the TGF-β1 receptor complex and triggers the activation of SMAD 2/3, which induces the expression of TGF-β1 target genes such as collagen and fibronectin.6 Previous studies revealed that impairment of TGF-β1 function resulted in the decreased production of collagen, the leading cause of thin, fragile skin and compromised wound healing, observed in aged human skin and UVB-exposed fibroblasts.28 In addition, the D
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PPARβ/δ Activity Assay. For the PPARβ/δ activity assay, 1× 104 cells per well were seeded in 48-well plates and allowed to attach overnight. The cells were then transfected with 0.2 μg of the PPRE3X-TK-luc plasmid (a kind gift from Dr. Christoper K. Glass, University of Califonia, San Diego, CA, USA) and 0.02 μg of pSG5PPARβ/δ expression vector (a kind gift from Han GeukSeo, Konkuk University, Seoul) using Lipofectamine 2000 transfection reagent (Promega, Madison, WI, USA) according to the manufacturer’s instruction. The pRL-CMV vector encoding renilla luciferase (0.01 μg) was cotransfected as an internal control of transfection efficiency. After incubating for 24 h, the cells were treated for 6 h with either 10 μM compound 1 or 10 μM GW501516 (Sigma-Aldrich), a known PPARβ/δ receptor agonist. Luciferase expression levels were measured using the Dual-Glo Luciferase Assay System (Promega) with a luminometer (Berthold Technologies GmbH & Co. KG, Bad Wildbad Germany). siRNA and Transfection. The synthetic short interfering RNAs (siRNA) and transfected mammalian cells for RNA interference study were obtained from Intergrated DNA Technologies (Coralville, IA, USA). The siRNA targeting human PPARβ/δ (NM_001171818) siRNA sequences used were as follows: antisense, 5′-AGACAGAUGCACCAACGAGGCUGAT-3′, and sense, 5′-CUUCUGUCUACGUGGUUGCUCCGACUA-3′. siRNAs were transfected using Lipofectamine 2000 (Invitrogen, Waltham, MA, USA) according to the manufacturer’s protocol. Staining of PPARβ/δ with Confocal Microscopy. Fibroblasts were seeded at a density of 1 × 105 cells in a coverglass-bottom dish, incubated overnight, and incubated with compound 1 or GW501516 for another 2 h. Then cells were fixed in 4% paraformaldehyde solution for 20 min at room temperature, washed with PBS, blocked with 3% normal goat serum (Gibco, Grand Island, NY, USA), and immunostained with rabbit anti-PPARβ/δ antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 4 °C overnight. Subsequently, cells were washed with Tris-buffered saline (TBS) and incubated for 3 h in the presence of Cy3-conjugated AffiniPure antirabbit IgG obtained from Jackson Immuno Research (West Grove, PA, USA). Cell nuclei were visualized by immunostaining with Hoechst 33342 (Invitrogen), and PPARβ/δ was examined by confocal laser scanning microscopy (TCS SP2, Leica, Wetzler, Germany). Extraction of Cytosolic and Nuclear Protein from Cells. Compound 1-treated fibroblasts were washed with PBS; then 1 mL of ice-cold PBS was added. Pellets were harvested at 1500g at 4 °C for 5 min. The pellets were then suspended in a hypotonic buffer, as previously described,13 and incubated on ice for 20 min. After incubation, 10% Nonidet P-40 (NP-40) solution was added and mixed for 15 s. The mixture was centrifuged at 14000g at 4 °C for 5 min. The supernatant was used as the cytosolic fraction, and the pellets were resuspended in nuclear extraction buffer, incubated on ice for 30 min, then centrifuged at 14000g at 4 °C for 15 min, as previously described.13 The supernatant was used as the nuclear fraction. Animals. Male Sprague−Dawley rats, 5 and 20 months old, were obtained from Samtako (Osan, Korea), and oral administration of 1 was induced as previously described.13 The animal protocol used in this study was reviewed and approved by the Pusan National University-Institutional Animal Care and Use Committee (PNUIACUC) for ethical procedures and animal care. Skin Tissue Homogenates and Western Blotting. Four hundred milligrams of frozen skin tissue was used to isolate subcellular fractions of cytosol and nuclei, as previously described.13 Western blotting was performed as previously described.15 Primary antibodies used are listed: COL1A1, COL3A1, TGF-β1, and PPARβ/δ (Santa Cruz Biotechnology). Statistical Analysis. The statistical significance of the differences between groups was determined by one-way analysis of variance (ANOVA) followed by a Bonferroni multiple comparison test. Values of p < 0.05 were considered statistically significant. Analyses were performed using GraphPad Prism 5 (GraphPad Software, La Jolla, CA, USA).
TGF-β1-induced pathway is impaired in naturally aged skin and UVB-irradiated cells, and this impairment contributes to the loss of type I collagen synthesis in aging skin.29 Accordingly, specific ligands for PPARβ/δ are proposed as promising therapeutic interventions for skin aging. The present study showed that 1-induced PPARβ/δ activation resulted in increased expressions of both TGF-β1 and type I and III collagen. Although the detailed mechanism of 1-induced TGFβ1 is yet to be determined, it is plausible that 1 may affect the activation of TGF-β1 signaling in fibroblasts. Most natural compounds used for skin antiaging are polyphenolic compounds because of their antioxidative capacity, but only a few of them are known to induce collagen synthesis.30,31 Our group recently showed that 1 has an antioxidant effect and that its antioxidative capacity prevents the expression of MMP through inhibiting NF-κB and AP-1 activation in UVB-exposed fibroblasts.13 MMPs are proteolytic enzymes that degrade ECM components such as collagen, elastin, and laminin and are involved in the turnover and remodeling of the dermis.32 UV irradiation activates MMPs that contribute to the breakdown of dermal interstitial collagen and other connective tissue components.15 There have been several reports showing that natural compounds protect UV-exposed skin from damage.13−15 On the basis of these reports and current data, we propose that 1 has an antiaging effect on skin by modulating the balance of tissue turnover, which in turn impacts its ability to mediate tissue homeostasis. In conclusion, the present study demonstrated that 1, through binding to PPARβ/δ, can significantly increase TGFβ1 and types I and III collagen expression in skin aging models. The results show that 1 has antiaging effects against intrinsic (natural changes) and extrinsic skin aging (UVB irradiation) and that 1 has a potential to be used as a novel therapeutic and cosmetic agent in antiaging skin products.
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EXPERIMENTAL SECTION
Chemicals. Compound 1 was kindly supplied by Takako Yokozawa (Toyama Medical and Pharmaceutical University, Toyama, Japan) and Takashi Tanaka (Nagasaki University, Nagasaki, Japan). The purity of 1 (99%) was determined by HPLC. Purification of magnesium lithospermate B from Salviae miltiorrhizae was reported previously.33 Chemical reagents were provided by Sigma-Aldrich (St. Louis, MO, USA). In Silico Protein−Ligand Docking Simulation. Docking simulation is a computer simulation technique that is used to model the interaction between nuclear hormone receptors and their ligands. Among the many tools available for in silico protein−ligand docking, AutoDock4.2 is the most commonly used because of its automated docking capabilities.34 Ligand docking was performed using a set of predefined three-dimensional (3D) grids of the target protein and a systemic search technique. To prepare for the docking procedure, the following procedures were performed: (1) two-dimensional (2D) structures were converted into 3D structures, (2) charges were calculated, and (3) hydrogen atoms were added using the ChemOffice program (http://www.cambridgesoft.com). Cell Culture and UVB Exposure. Hs27, a normal human foreskin fibroblast cell line, was purchased from American Type Culture Collection (ATCC) (Manassas, VA, USA). Cells were maintained in Dulbecco’s modified Eagle medium (DMEM) with 10% fetal bovine serum (HyClone, Laboratories Inc., Logan, UT, USA). Cells from passages 20 to 30 were used in this study. For UVB irradiation, a Cross-linker 800 series UVB light source (GEX-800, UVP, CA) equipped with 6 × 8 W lamps was used. The medium was changed to phosphate-buffered saline (PBS) before irradiation with UVB (30 mJ/ cm2). E
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AUTHOR INFORMATION
Corresponding Author
*Tel: +82 51 510 2814. Fax: +82 51 518 2821. E-mail:
[email protected]. Author Contributions ‡
Y. R. Jung and E. K. Lee contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) through grants from the Korea government (MSIP) (No. 2009-0083538) and the Basic Science Research Program through funding by the Ministry of Education (No. 2014R1A1A2008973). We are grateful to the Aging Tissue Bank for supplying research materials and information.
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REFERENCES
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