Cell Biochem Biophys (2015) 71:389–396 DOI 10.1007/s12013-014-0210-3

ORIGINAL PAPER

Gelsolin: Role of a Functional Protein in Mitigating Radiation Injury Mingjuan Li • Fengmei Cui • Ying Cheng • Ling Han • Jia Wang • Ding Sun • Yu-long Liu Ping-kun Zhou • Rui Min



Published online: 28 August 2014 Ó Springer Science+Business Media New York 2014

Abstract The present study was conducted to explore the protective effect of exogenous gelsolin (GSN) in mice exposed to high-dose of radiation. Changes in the levels of GSNs in peripheral blood of mice and cytoplasm of cultured human intestinal epithelial cells (HIECs) were analyzed after their exposure to different doses of 137Cs c-rays at a fixed dose rate. The coagulation associated indices, such as prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. Effect on radiation-mediated oxidative damage was evaluated by estimating the altered glutathione (GSH) and malondialdehyde (MDA) concentrations in the blood. The results showed that radiation induced a pronounced decrease in the pGSN blood levels. However, the cGSN levels of irradiated HIECs were increased in a dose-dependent manner. Administration of recombinant human pGSN to irradiated mice resulted in an ameliorated clotting time as indicated

Mingjuan Li and Fengmei Cui have contributed equally to this work. M. Li  Y. Cheng  L. Han  J. Wang  D. Sun  Y. Liu  R. Min (&) Division of Radiation Medicine Department of Naval Medicine, Second Military Medical University, Shanghai, China e-mail: [email protected] M. Li Medical Experimental Center, Medical College of JiaXing University, Jiaxing 314001, China F. Cui College of Radiation Medicine & Public Health, Soochow University, Suzhou, China P. Zhou (&) Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, China e-mail: [email protected]

by the PT and the APTT indices. The treatment of mice with hpGSN enhanced the blood levels of GSH while MDA concentrations were decreased indicating an improved antioxidant status. These results suggest that GSNs might play a regulatory role in the suppression of the tissue damage induced by acute radiation exposure. Keywords Gelsolin  Acute radiation injury  PT  APTT  GSH  MDA

Introduction Gelsolin (GSN) is an actin-modulating protein that can facilitate assembling of monomers to form filaments, block their polymerization by capping the peptide, and sever the existing filaments. These functions of gelsolin are meant to regulate actin dynamics involved in cell movement and transportation. Three isoforms of GSN, identified thus far, two cytoplasmic, and one secreted form present in the circulatory blood are encoded by a single gene located on chromosome 9 in human. The alternative transcriptional initiation and splicing is responsible for the generation of different isoforms in various tissues [1–3]. The plasma gelsolin (pGSN) differs from cytoplasmic gelsolin (cGSN) by the presence of a unique leader peptide (24 amino acids) at its N-terminal and a disulfide bond that provides it with an additional stability [4, 5]. In both adult and embryonic tissues, GSN is mainly expressed in the cells of mesenchymal–epithelial origin [6–9]. The cGSN is also highly expressed in platelets, macrophages and neutrophils, smooth muscle cells, and osteoblasts [10, 11]. However, secreted pGSN is mainly derived from the skeletal muscle [2]. Gelsolin-3, the second cytoplasmic and a minor isoform, differs from other cGSN by the presence of 11 amino

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acids at the N terminus. Gelsolin-3 is expressed predominantly in the brain oligodendrocytes and it has been indicated to be involved in myelin remodelling during spiralisation around axons [12]. Altered levels of pGSN have been linked to several pathological conditions, including acute liver injury, sepsis, myonecrosis, and trauma [13, 14]. The increased levels of pGSN reflect the severity of injuries, whereas the decreased levels of pGSN correlate with higher risk of mortality in intensive care unit patients [15, 16]. The cGSN has been found to be upregulated in different cell lines in response to oxidative stress induced by H2O2 treatment or in many diseases including Down’s syndrome. Levels of cGSN in children have been found to increase with growing age and in those suffering from of Down syndrome [17, 18]. One of the possible reasons for low or negligible levels of pGSN in individuals experiencing trauma or disease is that pGSN is consumed by its binding to actin, which is released from damaged cells [19]. Actin overload in trauma or disease may result in its accumulation in tissue gaps and cause vascular endothelial cell damage. Its release into the blood from the damaged tissue leads to obstruction of blood flow in the microvaculature [20, 21]. The pGSN is suggested to play a protective role against actin toxicity by binding with it to inhibit its polymerization [22, 23]. In addition, GSN has been found to possess antioxidant, antiinfection, and anti-apoptotic effects which are also exhibited in its anti-amyloidogenic/anti-Ab fibrillisation actions in reducing the amyloid load in the brains of Alzheimer’s patients and transgenic mouse model of the disease [24–26]. Accordingly, infusing recombinant pGSN attenuates the pathological symptoms of the diseases and reduces mortality [27]. In case of a nuclear disaster, rescue of the victims in critical condition and therapeutic measures to enhance their survival rate has continually been a matter of concern. The radiation injury could be acute caused by a direct exposure to high-dose radiation for a short duration, or chronic induced by the late and indirect action of various free radicals produced by radiation. Previously, major attention in the treatment and prevention of radiation injury was laid on the recovery of radiation-induced direct and acute effects, such as hematopoietic gastrointestinal and neurovascular damages. The secondary effects, such as microcirculation obstruction, depletion of antioxidant armory, inflammation, and metabolic dysfunctions were not addressed in the past. Nevertheless, now it has been realized that these secondary effects play a key role in the development of various pathologies including cancer. The radiation-induced free radicals mediate peroxidation of the membrane lipids causing altered membrane fluidity, permeability, and integrity that leads to cell dysfunctioning and death and release of cellular contents, such as actin [28].

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Considering the beneficial activities of GSN in trauma, we presumed that pGSN might play a protective role against radiation-induced secondary injury. In this study, we measured the effect of GSN on radiation-mediated changes in the plasma of mice and cytoplasm of cultured HIECs. We determined the effect of hpGSN on coagulation and antioxidant-related indices in the blood of mice and HIECs exposed to various radiation doses. The aim was to investigate if pGSN can be therapeutically used for mitigating the radiation damage.

Materials and Methods Reagents Recombinant human pGSN (hpGSN; 17.5 mg/ml saline plus 0.1 mM Ca2?) was a gift from Dr. Po-Shun Lee of Brigham & Women’s Hospital, Boston, Massachusetts, USA. The enzyme-linked immunosorbent assay (ELISA) kit used for the mouse pGSN test was purchased from Uscn Life Science, Inc. (Cat. No. E0372M; Wu Han, Hubei, China). Assay kits, and reagents for GSH and MDA were purchased from Nanjing KenGenBiltech Co. Ltd., (Nanjing, Jiangsu, China). Cell Culture and Irradiation HIECs (a gift from Professor P-k Zhou, Academy of Military Medical Science, Beijing) were cultured in RPMI1640 medium (PPA Laboratories GmbH, Cat. No E15–840) supplemented with 10 % foetal bovine serum and 0.625 % insulin at 37 °C, 5 % CO2 in a humidified incubator. The cells were exposed to 8 or 12 Gy of radiation at a dose rate of 1.0 Gy/min using a Gammacell 40 137Cs c-ray irradiator (Atomic Energy of Canada, Ltd., Ottawa, Ontario, Canada). The cells were incubated at 37 °C with 5 % CO2 for 2, 4, 6, 12, or 24 h post-irradiation and were harvested for subsequent analyses. Mice Irradiation Male BALB/c mice, weighing 22–24 g, (obtained from Shanghai SLAC Laboratory Animal Co. Ltd., Shanghai, China) were randomly divided into groups of control (nonirradiated), irradiated, and irradiated plus treated with hpGSN groups. Mice were subjected to whole-body exposure of 4 or 8 Gy of radiation for pGSN levels determination and 6 Gy for determining functional activities. Human pGSN (hpGSN) was administered (6 lg/g body weight) by injecting into the tail vein at 2 and 20 h after radiation exposure. For injections, each mouse was immobilised in a special tail vein-injection holding device, and the tail was stretched and sterilised. A 0.5-ml syringe with a size 4 needle

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was used for the injection. After determining whether the needle had penetrated the tail vein by drawing back of the blood stream, 65 ll of hpGSN solution was gently injected. All mice were provided with autoclaved standard rodent chow and water both before and after radiation exposure and were housed in a pathogen-free barrier facility (12-h light/ dark cycle). All of the experimental protocols involving mice were approved by Ethics Committee of the Second Military Medical University Determination of the cGSN and pGSN Levels Western blotting was used for measuring cGSN. Cells were lysed in a lysis buffer containing 1 mM phenylmethanesulfonyl fluoride (Beyotime Institute of Biotechnology, Nanjing, Jiangsu, China). The lysates were then

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APTT were determined using the STAGO STA-R Evolution system (Roche Diagnostics, Germany) at the Clinical Diagnosis Laboratory of Changhai Hospital, Shanghai. Plasma was prepared by adding anticoagulant to the blood. The PT and APTT were determined using standard analytical instruments. Measurement of GSH and MDA Levels The levels of GSH and MDA were determined using GSH and MDA assay kits following the manufacturer’s instructions (NanjinKenGenBiltech Co. Ltd., Nanjing, Jiangsu, China). The optical density (OD) was determined at 420 nm using a Multiskan Spectrophotometer and GSH and MDA level was calculated using the following formula:

test tube OD value  control tube OD value  20 lmol=l  GSHðFW 307Þ  dilution standard tube OD value  control tube OD value test tube OD value  Testing of control tube OD value MDAðnmol=mlÞ ¼  10 nmol=ml  dilution stand tube OD value  Testing of stand tube OD value

GSHðg=lÞ ¼

separated electrophoretically and transferred to nitrocellulose or reinforced nitrocellulose transfer membranes (Whatman Schleicher &Schuell BioScience GmbH, Hahnestrasse 3D-37586 Dassel, Germany). The membranes were blocked with 5 % skimmed milk in saline containing Tris buffer for 2 h at 4 °C and then incubated overnight with primary antibodies against GSN or b-actin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) at 4 °C. After three washes with Tris buffer-saline, the membranes were incubated with peroxidase-conjugated secondary antibodies (Protein Tech Group, Inc., Chicago, IL, USA) for 2 h at room temperature. The membrane was washed twice again, and the immunoreactive protein was visualised using an enhanced chemiluminescence reagent kit (Pierce, USA). Bands were quantified using the GeneTools manual band quantification software. All data shown are representative of the results of at least three separate experiments. The pGSN levels in mice plasma were determined using the Mouse Gelsolin ELISA kit. Blood was collected from the orbital veins at indicated time points after radiation and pGSN pGSN concentration was determined following the manufacturer’s instructions. Measurement of PT and APTT Blood was collected from the mice at the time points after radiation and centrifuged to obtain plasma. The PT and

Statistical Analysis Statistical analysis was performed with SPSS 13.00 software. Data are expressed as the mean ± standard deviation (SD) of six independent values. Student’s t test was used to compare the difference between two groups, Anova for comparison of over two groups. P value less than 0.05 was considered significant.

Results Changes of pGSN and cGSN Levels in Mice Blood After Irradiation Compared with the control group, the mice irradiated with 4 Gy showed significantly decreased levels of pGSN levels at 24 h post-irradiation that remained unchanged through 72 h (24 h: P = 0.01; 48 h: P = 0.02); 72 h: P = 0.02) (Fig. 1a). Immediately after radiation, the pGSN content was not different from that of the controls. However, the exposure to 8 Gy radiation resulted in a significant decline in the pGSN levels immediately after irradiation and further declined gradually and time dependently to the lowest value at 72 h (immediate: P = 0.05; 24 h: P = 0.03; 48 h: P = 0.03; 72 h: P = 0.002) (Fig. 1b).

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Fig. 1 Changes in the pGSN levels in the blood of irradiated mice. Mice were exposed to 4 and 8 Gy doses and blood was collected at different postirradiation times. Each group included 10 mice. Asterisks indicate significant differences compared with the control. The error bars indicate the standard deviation of the mean for three independent experiments

Fig. 2 cGSN content in irradiated HIECs as measured by Western blotting. b, d show the density values (cGSN/b-actin) of the protein bands in the Western blots (panels a and c). In a, c, lane 1 corresponds to the non-irradiated control, and lanes 2 through 6 correspond to the irradiated groups at 2, 4, 6, 12 and 24 h post-

irradiation, respectively. a, b represent the results from the cells exposed to 8 Gy of radiation, and c, d represent the results from the cells exposed to 12 Gy of radiation. Asterisks indicate that compared to the controls, the increase was significant

The cGSN content in HIECs was higher than that in blood. In order to ensure that the same bio-effect is produced as was in the whole body and changes in cGSN levels of the cells are detectable by Western blotting, we exposed the cells to 8 and 12 Gy radiations. The results showed that cGSN content decreased at 2, 4, 8, and 12 h of 8 Gy irradiation and significantly at 12 h of exposure. Interestingly, at 24 h of exposure with 8 Gy dose, the cGSN content was increased above that of the control (Fig. 2a, b). In 12 Gy exposure group, the cGSN level was slightly decreased at 2 h post-irradiation, and then it elevated gradually with increasing time and reached to significantly higher levels than those observed in the control group or at 6, 12, and 24 h post-irradiation (Fig. 2c, d).

hpGSN Administration Improved the Clotting Indices

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Bleeding is a common pathological event associated with damage caused by heavy radiation in human and animal models. To evaluate the effect of hpGSN on radiationinduced bleeding, PT and APTT were estimated (Fig. 3). A mouse model of severe bone marrow-type acute radiation sickness (ARS) was exposed to whole-body radiation at a dose of 6 Gy. Compared with the irradiation alone group, PT in the mice treated with hpGSN after radiation increased significantly in the 4–7 days group (P = 0.04) (Fig. 3a) and significantly decreased in the 14–18 days group (P = 0.04) (Fig. 3b). The changes in APTT showed similar pattern as that of PT. Compared with the mice treated with radiation alone, the mice supplemented with

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Fig. 3 Changes of blood coagulation indicators PT and APTT. The radiation exposed mice were treated with 6 Gy c rays, hpGSN was given after irradiation. Blood samples were collected on days 4 (6 mice per group), 7 (5 mice per group), 14 (5 mice per group), 16 (4 mice per group) and 18 (4 mice per group) post-irradiation

Fig. 4 Effect of hpGSN on Blood GSH and MDA levels of radiation-exposed mice. Blood samples were collected on days 2 and 7 after 6 Gy radiation exposure. The number of mice in gelsolin plus radiation, radiation alone, and untreated control groups were 8, 16 and 8 respectively

hpGSN after irradiation showed significantly increased APTT in the 4–7 days group (P = 0.03) (Fig. 3c) and significantly decreased in the 14–18 days group (P = 0.03) (Fig. 3d). Asterisks indicate significant differences between the groups.

Oxidative Stress Indices were Improved with hpGSN Supplementation The blood GSH levels were significantly lowered in the mice irradiated with 6 Gy on days 2 and 7 post exposure,

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the durations that represent early to mid-phases of severe bone marrow-type ARS. Blood levels of GSH measured at days 2 and 7 or irradiation were substantially reduced. In mice treated with hpGSN, GSH levels were recovered and the effect was significant at day 7 (P = 0.02) (Fig. 4a, b). Similarly, the radiation-mediated marked increase in malondialdehyde (MDA) concentration was completely reversed back to control levels on day 7 (P = 0.01).

Discussion Considerably low levels of blood GSN in trauma, burns, major surgery, or hematopoietic stem cell transplantation are associated with poor outcomes, including death [29]. Owing to its crucial protective role against sepsis-induced actin toxicity, use of gelsoline has been suggested as a potential therapy in this lethal condition [30]. However, the role of gelsoline in radiation caused injury has scarcely been studied. The ARS patients suffer from heavy bone marrow damage, and multiple organ dysfunction (MOD) has been considered a major cause of their death. An abnormal release of actin from dead- and damaged-cells is a common event in these pathological injuries. A persisting presence of circulating actin microfilaments has been known to play a crucial role in multiple organ dysfunction syndrome (MODS) [26, 31]. Clinical studies have also shown that high levels of circulating actin that exceed the functional ability of the scavenging system contribute to actin-associated microemboli formation and activation of the platelets [32]. The severing of filamentous actin (F-actin) and converting it into globular form (G-actin) is one of the important functions of GSN [33]. The decreased blood levels of pGSN in irradiated mice in the present study might have resulted, at least in part from an overconsumption of pGSN in scavenging an overload of actin released from the damaged cells. The consistent decrease of pGSN level in mice exposed to acute radiation observed in the present study suggests the role of pGSN in the progression of injury. Radiation is known to mediate injury through oxidative stress and many lines of evidence have confirmed the antioxidant properties of GSN [18, 28, 33, 34]. The involvement of cGSN in the oxidation/reduction reactions through its five free thiol groups (cysteinyl) seems to be quite possible. Moreover, pGSN has three free thiol groups that can markedly inhibit platelet activating factor (PAF)induced superoxide anion (O2-) production in human peripheral neutrophils in a concentration-dependent manner [35]. The changes in plasma GSH and MDA levels in the hpGSN-treated group observed in the present study suggest that pGSN may relieve oxidative stress via

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suppressing lipid peroxidation and enhancing the generation of GSH, a vital antioxidant. These results completely agree with those reported in a previous study wherein changes in pGSN concentrations were found to be associated with an acute oxidative lung injury [34]. The effect of radiation on cytoplasmic cGSN was also investigated in the radiosensitive HIEC cells. Our results demonstrated that irradiated cells showed a dose- and timedependent increase in their cGSN content, and the effect was significant. The increased levels of cGSN in various conditions have previously been associated with its antioxidant activity [18, 33–35]. The radiation-induced increase in cGSN content of the cells observed in the present study might also be explained as antioxidant defense response triggered to combat the oxidative damage. Bleeding is one of the most serious consequences of heavy bone marrow-type acute radiation injury and it is also one of the main causes of mortality. The function of pGSN in blood coagulation has not been completely understood. The antiphospholipid syndrome, characterized by repeated thrombotic episodes is marked by the presence of antiphospholipid antibodies (aPLs). These antibodies have been reported to be predominantly directed to various target antigens including prothrombin [36]. The aPLs have also been shown to induce the expression of tissue factor, the major initiator of extrinsic coagulation cascade in monocytes. The involvement of pGSN has been proposed in the complex interaction of many endogenous proteins that promotes prothrombotic state [30]. Actin filaments in plasma are also known to activate platelets and slow down fibrinolysis by binding to plasmin [20]. In order to determine whether GSN participates in the regulation of blood coagulation, we measured PT and APTT in the ARS mice obtained by exposure to radiations at a dose of 6 Gy. In this ARS mouse model, 4–7 days post-exposure roughly corresponded to mid-phase, and 14–18 days post-exposure corresponded to critical phase of a heavy bone marrowtype ARS in clinical conditions. The suppression of radiation-mediated increase of PT and APTT indicated that pGSN does play a regulatory role in the recovery of coagulation time. Administration of pGSN was not effective in improving the bleeding tendency on 4–7 days postirradiation, that is, the early- and mid-pathological phases of acute radiation injury. However, at 14–18 days postirradiation, during the later phases of the bone marrow-type ARS, treatment with exogenous pGSN ameliorated the bleeding tendency as indicated by decreased PT and APTT. However, the mechanism of pGSN-exerted normalization of PT and APTT during the progression of different phases of ARS remains to be elucidated. The changes in GSN levels, observed in our study, in both blood and cytoplasm indicate the effectiveness of GSN against acute radiation damage. The exogenous

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administration of recombinant pGSN to irradiated mice suppressed action was evidenced as enhanced antioxidant status of the cells. It also showed recovery of radiationinduced prolonged bleeding time in the late phase of acute radiation injury. Taken together, the present data, suggest that GSN has a potential of therapeutic usage in mitigating the acute radiation damage.

Conclusions These results clearly suggest that GSN has a potential to block the radiation-induced injury. Furthermore, these observations propose that the beneficial effect of pGSN is mediated through suppression of lipid peroxidation, an enhancement of antioxidant generation and blockade of the bleeding time prolongation. Acknowledgments The research was supported by the National Natural Science Fund 81372932 and Army Force Fund BWS11J009. We thank Dr.Po-shun Lee (Brigham and Women’s hospital, Boston, MA) for valuable suggestions and providing us with the recombiant human gelsolin and also thank Dr. Thomas P.Stossel(Brigham and Women’s Hospital, Boston, MA) and Susan Goelz (Biogen,Cambridge, MA) for their interest in this work and for providing useful advice. Conflict of interest The authors declare that they have no competing interests, including, but not limited to, conflicts of interest regarding the gift of gelsolin.

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Gelsolin: role of a functional protein in mitigating radiation injury.

The present study was conducted to explore the protective effect of exogenous gelsolin (GSN) in mice exposed to high-dose of radiation. Changes in the...
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