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IDH2 Deficiency Impairs Cutaneous Wound Healing Via ROS-Dependent

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IDH2 Deficiency Impairs Cutaneous Wound Healing Via ROS-Dependent BBA - Molecular Basis of Disease 1865 (2019) 165523 Contents lists available at ScienceDirect BBA - Molecular Basis of Disease journal homepage: www.elsevier.com/locate/bbadis IDH2 deficiency impairs cutaneous wound healing via ROS-dependent apoptosis T ⁎ Sung Hwan Kim, Jeen-Woo Park School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea ARTICLE INFO ABSTRACT Keywords: Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue that play a Wound healing pivotal role in cutaneous wound healing by synthesizing fibronectin (a component of the extracellular matrix), Apoptosis secreting angiogenesis factors, and generating strong contractile forces. In wound healing, low concentrations of IDH2 reactive oxygen species (ROS) are essential in combating invading microorganisms and in cell-survival signaling. Mitochondria However, excessive ROS production impairs fibroblasts. Mitochondrial NADP+-dependent isocitrate dehy- Mito-TEMPO drogenase (IDH2) is a key enzyme that regulates the mitochondrial redox balance and reduces oxidative stress- induced cell injury through the generation of NADPH. In the present study, the downregulation of IDH2 ex- pression resulted in an increase in cell apoptosis in mouse skin through ROS-dependent ATM-mediated p53 signaling. IDH2 deficiency also delayed cutaneous wound healing in mice and impaired dermal fibroblast function. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO alleviated the apoptosis induced by IDH2 deficiency both in vitro and in vivo. Together, our findings highlight the role of IDH2 in cutaneous wound healing in association with mitochondrial ROS. 1. Introduction expression, while also stimulating the proliferation and migration of fibroblasts, leading to the formation of the extracellular matrix (ECM). Skin is a barrier system that protects the body from injuries, bac- At the same time, keratinocyte proliferation and migration are pro- terial infiltration, and the loss of water. When the skin is injured, fi- moted, facilitating re-epithelialization. However, excessive ROS pro- broblasts play a pivotal role in cutaneous wound healing by pro- duction leads to oxidative stress that can, directly and indirectly, liferating and migrating to the wound bed, where they produce modify and degrade ECM proteins and also impair fibroblasts and extracellular matrix proteins, such as fibronectin, form granulation keratinocytes [4]. tissue, and generate strong contractile forces to draw the wound mar- Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) gins toward one another. When the wound has been replaced with a controls the energy and redox status and catalyzes the oxidative dec- fibrotic scar, the fibroblasts are removed via apoptosis [1–3]. arboxylation of isocitrate to α-ketoglutarate, thus producing NADPH, a Reactive oxygen species (ROS) are generated by cellular metabo- cofactor that is fundamental for the regeneration of the thioredoxin lism, particularly within the mitochondria. Growing evidence suggests system [6] and for maintaining the pool of reduced glutathione (GSH). that ROS are crucial regulators of several phases of the healing process, Glutathione reductase generates GSH via the NADPH-dependent re- with low concentrations of ROS necessary to repel invading micro- cycling of oxidized glutathione (GSSG). When under oxidative stress, organisms and involved in cell survival signaling [4]. In the early stages GSSG accumulates and alters the mitochondrial GSH to GSSG ratio, of wound healing, ROS initiate platelet aggregation and stimulate the which serves as a marker for cellular oxidative stress [7]. Therefore, in diapedesis of adherent leukocytes across the blood vessel wall in order providing NADPH for NADPH-dependent antioxidant enzymes, IDH2 to kill microorganisms at the site of the injury. ROS also promote fi- plays an important role in regulating the mitochondrial redox balance broblast proliferation and migration and mediate TGF-β1 signaling, and reducing oxidative stress-induced cell damage [8]. It has also been which results in the production of fibronectin and the expression of reported that IDH2-knockout mice develop heart failure, heart cell growth factors [4,5]. In addition, ROS has been shown to stimulate apoptosis, and hypertrophy [7]. IDH2 deficiency also induces en- angiogenesis, endothelial cell division and migration via VEGF dothelial dysfunction by causing dynamic mitochondrial changes and ⁎ Corresponding author. E-mail address: [email protected] (J.-W. Park). https://doi.org/10.1016/j.bbadis.2019.07.017 Received 29 April 2019; Received in revised form 29 July 2019; Accepted 30 July 2019 Available online 31 July 2019 0925-4439/ © 2019 Elsevier B.V. All rights reserved. S.H. Kim and J.-W. Park BBA - Molecular Basis of Disease 1865 (2019) 165523 impairing vascular function [9]. However, the effect of IDH2 on cuta- (Cambridge, UK); oxidized peroxiredoxin (Prx-SO3, LF-PA0004) from neous wound healing has yet to be elucidated. With this in mind, we AbFrontier (Seoul, Korea); IDH2 (SAB2501533) from Sigma Aldrich (St. demonstrated that IDH2-deficient mice exhibit delayed cutaneous Louis, MO); and HSP47 (SC-5293), phospho-p53 (SC-71786), fi- wound healing due to impaired dermal fibroblast function. In parti- bronectin (SC-8422), collagen 6 (SC-377143), PECAM (SC-376764), cular, IDH2 deficiency induced p53-mediated apoptosis through the and β-actin (SC-47778) from Santa Cruz Biotechnology (Santa Cruz, modulation of ROS-dependent p53 signaling. This study confirmed that CA). Dermal fibroblasts were fixed with 3% formaldehyde in PBS for IDH2 plays an important role in wound healing. 15 min at room temperature and gently washed twice with PBS. Acetone permeabilization was performed with 100% ice-cold acetone at 2. Materials and methods −20 °C for 10 min. After fixation, immunostaining was conducted as previously described [7]. Wound specimens were fixed in 4% for- 2.1. Animal preparation maldehyde and then embedded with paraffin, and 5-μm sections were sliced. Each slide was subjected to deparaffinization and rehydration, Experiments were performed using 8-week-old male C57BL/6 mice, followed by antigen unmasking. The sections were boiled at 98 °C in a − − consisting of wild-type (WT) Idh2+/+ and knockout (KO) Idh2 / 10 mM sodium citrate buffer for 10 min and cooled for 20 min. Im- genotypes generated by breeding and identified by PCR genotyping, as munostaining was conducted as previously described [12]. To de- previously described [10]. For mito-TEMPO experimentation, the mice termine skin morphology, wound specimens were sequentially stained received a daily injection of mito-TEMPO (0.7 mg/kg, intraperitoneal) with hematoxylin Gill No. 3, bluing solution, and eosin Y via gentle starting at week 6 for 30 days. The mice were allowed free access to shaking at room temperature. Connective tissue (i.e., dermis and hy- water and standard mouse chow. The temperature (23 ± 2 °C), hu- podermis) regeneration in the wound was assessed following trichrome midity (50 ± 5%), and daily 12 h light–dark cycle was kept constant in staining with a Masson trichrome staining kit. The collagen fibers of the the Central Laboratory Animal Facility at Kyungpook National Uni- connective tissue within the dermis and hypodermis were stained blue. versity. All animal procedures were conducted in accordance with the Institutional Animal Care guidelines issued by the Committee of Animal 2.6. Immunoblot analysis Research at Kyungpook National University. The following commercial antibodies were used for immunoblot 2.2. Primary cells culture analysis in the present study: VEGF (SC-152) (Cell Signaling Technology); phospho-Chk2 (ab59408), phospho-E2F1 (ab55325) and +/+ Primary dermal fibroblasts from wild-type (WT) Idh2 and α-SMA (ab5694) (Abcam); Prx-SO3 (LF-PA0004) (AbFrontier); IDH2 − − knockout (KO) Idh2 / mice were established via the enzymatic di- (SAB2501533) (Sigma Aldrich); and HSP47 (SC-5293), phospho-p53 gestion of the dorsal dermal skin using collagenase I [11]. Primary (SC-71786), fibronectin (SC-8422), collagen 6 (SC-377143), PECAM murine dermal fibroblasts were maintained in DMEM/F12 containing (SC-376764), phospho-ATM (SC-47739), and β-actin (SC-47778). 15% FBS and 1% of an antibiotic/antimycotic mixture in a humidified Conventional immunoblotting procedures were used to detect the incubator at 37 °C and 5% CO2. target proteins. The cells were collected, washed once in cold PBS, and then scraped in a TEGN buffer (10 mM Tris, pH 8, 1 mM EDTA, 10% 2.3. Excisional wound preparation glycerol, 0.5% Nonidet P-40, 400 mM NaCl, 1 mM DTT, 0.5 mM phe- nylmethylsulfonylfluoride, and protease inhibitor mixture containing The hair of the back of the mouse was shaved with electric clippers 1 M benzamidine, 3 mg/mL leupeptin, 100 mg/ mL bacitracin, and followed by the application of depilatory cream. To make an excisional 1 mg/mL α2 macroglobulin) and incubated on ice for 15 min. Lysates wound, the skin was first rinsed with alcohol, and sterile skin biopsy were then cleared using centrifugation at 20,000g for 10 min. The total punches (Miltex Inc., York, PA) with a diameter of 5 mm were then used protein concentration was determined using Bio-Rad protein assays. to create four full-thickness skin wounds on the dorsal surface (back) of Equal amounts of protein were separated on 10% SDS-PAGE and the the mouse. Following this, the mice were caged individually, and the proteins were transferred to nitrocellulose membranes (Bio-Rad). The wounds were not dressed. membranes were then blocked for 1 h in a PBS solution containing 5% nonfat milk powder and 0.1% Tween-20 and then probed with primary 2.4. RNA isolation and reverse transcription (RT)-PCR antibodies overnight in 1% milk and 0.1% Tween-20 in PBS. After washing, the membranes were incubated for 1 h with a horseradish To extract mRNA, a piece of whole skin (1 cm × 1 cm) was treated peroxidase-linked secondary antibody (Sigma Aldrich) in 1% milk and with 500 μL of TRIzol reagent and incubated for 30 min at room tem- 0.1% Tween-20 in PBS.
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