Publications by authors named "Hyun Kyo Lim"

41 Publications

Arginase inhibition by rhaponticin increases L-arginine concentration that contributes to Ca2+-dependent eNOS activation.

BMB Rep 2021 Jun 3. Epub 2021 Jun 3.

Department of Biological Sciences, Kangwon National University, Chuncheon 24341, Korea.

Although arginase primarily participates in the last reaction of the urea cycle, we have previously demonstrated that arginase II is an important cytosolic calcium regulator through spermine production in a p32-dependent manner. Here, we demonstrated that rhaponticin (RPT) is a novel medicinal-plant arginase inhibitor and investigated its mechanism of action on Ca2+-dependent endothelial nitric oxide synthase (eNOS) activation. RPT was uncompetitively inhibited for both arginases I and II prepared from mouse liver and kidney. It also inhibited arginase activity in both aorta and human umbilical vein endothelial cells (HUVECs). Using both microscope and FACS analyses, RPT treatments induced increases in cytosolic Ca2+ levels using Fluo-4 AM as a calcium indicator. Increased cytosolic Ca2+ elicited the phosphorylations of both CaMKII and eNOS Ser1177 in a time-dependent manner. RPT incubations also increased intracellular L-arginine (L-Arg) levels and activated the CaMKII/AMPK/Akt/eNOS signaling cascade in HUVECs. Treatment of L-Arg and ABH, arginase inhibitor, increased intracellular Ca2+ concentrations and activated CaMKII-dependent eNOS activation in ECs of WT mice, but, the effects were not observed in ECs of inositol triphosphate receptor type 1 knockout (IP3R1-/-) mice. In the aortic endothelium of WT mice, RPT also augmented nitric oxide (NO) production and attenuated reactive oxygen species (ROS) generation. In a vascular tension assay using RPT-treated aortic tissue, cumulative vasorelaxant responses to acetylcholine (Ach) were enhanced, and phenylephrine (PE)-dependent vasoconstrictive responses were retarded, although sodium nitroprusside and KCl responses were not different. In this study, we present a novel mechanism for RPT, as an arginase inhibitor, to increase cytosolic Ca2+ concentration in a L-Arg-dependent manner and enhance endothelial function through eNOS activation.
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June 2021

Complications of fluid overload during hysteroscopic surgery: cardiomyopathy and epistaxis - A case report.

Anesth Pain Med (Seoul) 2020 Jan;15(1):61-65

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Background: Hysteroscopic surgery has been used in various gynecological fields. However, massive fluid overload can occur as a complication due to persistent infusion of media for uterine cavity distension. We present the case of a woman who developed cardiomyopathy with pulmonary edema and epistaxis during hysteroscopic surgery.

Case: A 76-year-old female underwent hysteroscopic septectomy. She manifested abrupt, active nasal bleeding and regurgitation in the intravenous line. Heart rate, SpO, and PETCO decreased from 55 beats/min to 29 beats/min, from 100% to 56%, and from 31 mmHg to 9 mmHg, respectively. After the operation, brain CT showed bilateral prominent superior ophthalmic vein dilation. Echocardiography showed left ventricle apical ballooning and global hypokinesia. The patient recovered after two days of conservative management, with no sequelae.

Conclusions: Although hysteroscopic surgery is a simple procedure, careful monitoring is necessary to prevent complications from absorption of fluid distending media during the procedure.
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http://dx.doi.org/10.17085/apm.2020.15.1.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713864PMC
January 2020

The efficacy of intramuscular ephedrine in preventing hemodynamic perturbations in patients with spinal anesthesia and dexmedetomidine sedation.

Int J Med Sci 2020 25;17(15):2285-2291. Epub 2020 Aug 25.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, Republic of Korea.

Dexmedetomidine is used for sedation during spinal anesthesia. The sympatholytic effect of dexmedetomidine may exacerbate hypotension and bradycardia with spinal anesthesia. This study investigated the effects of prophylactic intramuscular injection of ephedrine in preventing hypotension and bradycardia occurring through combined use of spinal anesthesia and dexmedetomidine. One hundred sixteen patients scheduled for lower extremity orthopedic surgery were randomized into two groups receiving either ephedrine 20 mg intramuscularly or equivalent amount of 0.9% NaCl, both with dexmedetomidine and spinal anesthesia. The primary endpoint was the incidence of hemodynamic perturbations (hypotension or bradycardia event). The secondary endpoint was a rescue doses of ephedrine and atropine. The incidence of hemodynamic perturbations was significantly lower in the ephedrine group compared with to the saline group (26.3% versus 55.9%, p = 0.001). The rescue doses of atropine (0.09 ± 0.21 versus 0.28 ± 0.41, p = 0.001) and ephedrine (1.04 ± 2.89 versus 2.03 ± 3.25, p = 0.007) were also significantly lower in the ephedrine group. There was no differences in number of patients with hypertensive (7.0% versus 11.9%, p = 0.375) or tachycardia (1.8% versus 3.4% p = 0.581) episodes. The use of ephedrine intramuscular injections may be a safe and efficacious option in preventing hemodynamic perturbations in patients who received spinal anesthesia and sedation using dexmedetomidine.
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http://dx.doi.org/10.7150/ijms.48772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484642PMC
July 2021

Overexpressed p32 localized in the endoplasmic reticulum and mitochondria negatively regulates calcium‑dependent endothelial nitric oxide synthase activit.

Mol Med Rep 2020 Sep 6;22(3):2395-2403. Epub 2020 Jul 6.

Department of Biological Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.

The p32 protein plays a crucial role in the regulation of cytosolic Ca2+ concentrations ([Ca2+]c) that contributes to the Ca2+‑dependent signaling cascade. Using an adenovirus and plasmid p32‑overexpression system, the aim of the study was to evaluate the role of p32 in the regulation of [Ca2+] and its potential associated with Ca2+‑dependent endothelial nitric oxide synthase (eNOS) activation in endothelial cells. Using electron and confocal microscopic analysis, p32 overexpression was observed to be localized to mitochondria and the endoplasmic reticulum and played an important role in Ca2+ translocation, resulting in increased [Ca2+] in these organelles and reducing cytosolic [Ca2+] ([Ca2+]c). This decreased [Ca2+]c following p32 overexpression attenuated the Ca2+‑dependent signaling cascade of calcium/calmodulin dependent protein kinase II (CaMKII)/AKT/eNOS phosphorylation. Moreover, in aortic endothelia of wild‑type mice intravenously administered adenovirus encoding the p32 gene, increased p32 levels reduced NO production and accelerated reactive oxygen species (ROS) generation. In a vascular tension assay, p32 overexpression decreased acetylcholine (Ach)‑induced vasorelaxation and augmented phenylephrine (PE)‑dependent vasoconstriction. Notably, decreased levels of arginase II (ArgII) protein using siArgII were associated with downregulation of overexpressed p32 protein, which contributed to CaMKII‑dependent eNOS phosphorylation at Ser1177. These results indicated that increased protein levels of p32 caused endothelial dysfunction through attenuation of the Ca2+‑dependent signaling cascade and that ArgII protein participated in the stability of p32. Therefore, p32 may be a novel target for the treatment of vascular diseases associated with endothelial disorders.
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http://dx.doi.org/10.3892/mmr.2020.11307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411372PMC
September 2020

Federated Reinforcement Learning for Training Control Policies on Multiple IoT Devices.

Sensors (Basel) 2020 Mar 2;20(5). Epub 2020 Mar 2.

Department of Computer Science Engineering, Korea University of Technology and Education, Cheonan 31253, Korea.

Reinforcement learning has recently been studied in various fields and also used to optimally control IoT devices supporting the expansion of Internet connection beyond the usual standard devices. In this paper, we try to allow multiple reinforcement learning agents to learn optimal control policy on their own IoT devices of the same type but with slightly different dynamics. For such multiple IoT devices, there is no guarantee that an agent who interacts only with one IoT device and learns the optimal control policy will also control another IoT device well. Therefore, we may need to apply independent reinforcement learning to each IoT device individually, which requires a costly or time-consuming effort. To solve this problem, we propose a new federated reinforcement learning architecture where each agent working on its independent IoT device shares their learning experience (i.e., the gradient of loss function) with each other, and transfers a mature policy model parameters into other agents. They accelerate its learning process by using mature parameters. We incorporate the actor-critic proximal policy optimization (Actor-Critic PPO) algorithm into each agent in the proposed collaborative architecture and propose an efficient procedure for the gradient sharing and the model transfer. Using multiple rotary inverted pendulum devices interconnected via a network switch, we demonstrate that the proposed federated reinforcement learning scheme can effectively facilitate the learning process for multiple IoT devices and that the learning speed can be faster if more agents are involved.
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http://dx.doi.org/10.3390/s20051359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085801PMC
March 2020

Arginase II activity regulates cytosolic Ca level in a p32-dependent manner that contributes to Ca-dependent vasoconstriction in native low-density lipoprotein-stimulated vascular smooth muscle cells.

Exp Mol Med 2019 06 3;51(6):1-12. Epub 2019 Jun 3.

Department of Biology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.

Although arginase II (ArgII) is abundant in mitochondria, Ca-accumulating organelles, the relationship between ArgII activity and Ca translocation into mitochondria and the regulation of cytosolic Ca signaling are completely unknown. We investigated the effects of ArgII activity on mitochondrial Ca uptake through mitochondrial p32 protein (p32m) and on CaMKII-dependent vascular smooth muscle cell (VSMC) contraction. Native low-density lipoprotein stimulation induced an increase in [Ca]m as measured by CoCl-quenched calcein-AM fluorescence, which was prevented by Arg inhibition in hAoSMCs and reduced in mAoSMCs from ArgII mice. Conversely, [Ca]c analyzed with Fluo-4 AM was increased by Arg inhibition and ArgII gene knockout. The increased [Ca]c resulted in CaMKII and MLC 20 phosphorylation, which was associated with enhanced vasoconstriction activity to phenylephrine (PE) in the vascular tension assay. Cy5-tagged siRNA against mitochondrial p32 mRNA (sip32m) abolished mitochondrial Ca uptake and induced activation of CaMKII. Spermine, a polyamine, induced mitochondrial Ca uptake and dephosphorylation of CaMKII and was completely inhibited by sip32m incubation. In mAoSMCs from ApoE-null mice fed a high-cholesterol diet (ApoE +HCD), Arg activity was increased, and spermine concentration was higher than that of wild-type mice. Furthermore, [Ca]m and p32m levels were elevated, and CaMKII phosphorylation was reduced in mAoSMCs from ApoE +HCD. In vascular tension experiments, an attenuated response to vasoconstrictors in de-endothelialized aorta from ApoE +HCD was recovered by incubation of sip32m. ArgII activity-dependent production of spermine augments Ca transition from the cytosol to the mitochondria in a p32m-dependent manner and regulates CaMKII-dependent constriction in VSMCs.
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http://dx.doi.org/10.1038/s12276-019-0262-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545325PMC
June 2019

Resveratrol is an arginase inhibitor contributing to vascular smooth muscle cell vasoconstriction via increasing cytosolic calcium.

Mol Med Rep 2019 May 14;19(5):3767-3774. Epub 2019 Mar 14.

Department of Biology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.

The contractility of vascular smooth muscle cells (VSMCs) controls the lumen diameter of vessels, thus serving a role in regulating blood pressure and organ blood flow. Although arginases are known to have numerous effects in the biological activities of VSMCs, the effects of arginase II on the constriction of VSMCs has not yet been investigated. When conducting a natural products screen for an inhibitor against arginase, the present study identified that a relatively high concentration of resveratrol (RSV) exhibited arginase inhibitory activity. Therefore, the present study investigated whether RSV could regulate VSMCs contractions and the underlying mechanism. Arginase inhibition by RSV led to an increase in the concentration of the substrate L‑Arg and an accompanying increase in the cytosol Ca2+ concentration [(Ca2+)c] in VSMCs. The increased [Ca2+]c induced by RSV and L‑Arg treatments resulted in CaMKII‑dependent MLC20 phosphorylation. The effects of RSV on VSMCs were maintained even when VSMCs were pre‑treated with sirtinol, an inhibitor of Sirt proteins. In a vascular tension assay with de‑endothelialized aortic vessels, vasoconstrictor responses, which were measured using phenylephrine (PE), were significantly enhanced in the RSV‑ and L‑Arg‑treated vessels. Therefore, although arginase inhibition has exhibited beneficial effects in various diseases, care is required when considering administration of an arginase inhibitor to patients with vessels endothelial dysfunction as RSV can induce vessel contraction.
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http://dx.doi.org/10.3892/mmr.2019.10035DOI Listing
May 2019

Arginase II Contributes to the Ca/CaMKII/eNOS Axis by Regulating Ca Concentration Between the Cytosol and Mitochondria in a p32-Dependent Manner.

J Am Heart Assoc 2018 09;7(18):e009579

1 Department of Biology School of medicine Kangwon National University Chuncheon Korea.

Background Arginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase ( eNOS ). We tested the hypotheses that arginase II activity participates in the regulation of Ca/Ca/calmodulin-dependent kinase II / eNOS activation, and this process is dependent on mitochondrial p32. Methods and Results Downregulation of arginase II increased the concentration of cytosolic Ca ([Ca]c) and decreased mitochondrial Ca ([Ca]m) in microscopic and fluorescence-activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca/Ca/calmodulin-dependent kinase II . These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II -null mice resulted in reduced p32 protein level. In the aortas of wild-type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO -dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca]m were increased in the aortas from apolipoprotein E (ApoE) mice fed a high-cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca/Ca/calmodulin-dependent kinase II -dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice. Conclusions These data demonstrate a novel function of arginase II in regulation of Ca-dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.
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http://dx.doi.org/10.1161/JAHA.118.009579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222941PMC
September 2018

Arginase Inhibition Suppresses Native Low-Density Lipoprotein-Stimulated Vascular Smooth Muscle Cell Proliferation by NADPH Oxidase Inactivation.

Yonsei Med J 2018 May;59(3):366-375

Department of Biological Sciences, Kangwon National University, Chuncheon, Korea.

Purpose: Vascular smooth muscle cell (VSMC) proliferation induced by native low-density lipoprotein (nLDL) stimulation is dependent on superoxide production from activated NADPH oxidase. The present study aimed to investigate whether the novel arginase inhibitor limonin could suppress nLDL-induced VSMC proliferation and to examine related mechanisms.

Materials And Methods: Isolated VSMCs from rat aortas were treated with nLDL, and cell proliferation was measured by WST-1 and BrdU assays. NADPH oxidase activation was evaluated by lucigenin-induced chemiluminescence, and phosphorylation of protein kinase C (PKC) βII and extracellular signal-regulated kinase (ERK) 1/2 was determined by western blot analysis. Mitochondrial reactive oxygen species (ROS) generation was assessed using MitoSOX-red, and intracellular L-arginine concentrations were determined by high-performance liquid chromatography (HPLC) in the presence or absence of limonin.

Results: Limonin inhibited arginase I and II activity in the uncompetitive mode, and prevented nLDL-induced VSMC proliferation in a p21Waf1/Cip1-dependent manner without affecting arginase protein levels. Limonin blocked PKCβII phosphorylation, but not ERK1/2 phosphorylation, and translocation of p47phox to the membrane was decreased, as was superoxide production in nLDL-stimulated VSMCs. Moreover, mitochondrial ROS generation was increased by nLDL stimulation and blocked by preincubation with limonin. Mitochondrial ROS production was responsible for the phosphorylation of PKCβII. HPLC analysis showed that arginase inhibition with limonin increases intracellular L-arginine concentrations, but decreases polyamine concentrations. L-Arginine treatment prevented PKCβII phosphorylation without affecting ERK1/2 phosphorylation.

Conclusion: Increased L-arginine levels following limonin-dependent arginase inhibition prohibited NADPH oxidase activation in a PKCβII-dependent manner, and blocked nLDL-stimulated VSMC proliferation.
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http://dx.doi.org/10.3349/ymj.2018.59.3.366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889988PMC
May 2018

Wound Healing Effect of Slightly Acidic Electrolyzed Water on Cutaneous Wounds in Hairless Mice via Immune-Redox Modulation.

Biol Pharm Bull 2017 ;40(9):1423-1431

Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University.

Acidic electrolyzed water is an innovative sanitizer having a wide-spectrum of applications in food industry, and healthcare industry but little is known on its effect and mechanism in wound healing. The study was conducted to identify the effect and mechanism of slightly acidic electrolyzed water (SAEW) on cutaneous wounds in hairless mice. SAEW (pH: 5-6.5, oxidation reduction potential: 800 mV, chlorine concentration: 25 ppm) was prepared through electrolysis of water and was applied to the wounds of hairless mice three times a day for seven days. Wound size, immune response and oxidative stress were explored and compared to conventional agents such as Betadine and alcohol. We found that SAEW-treated group showed the highest wound reduction percentage (p<0.01). Antioxidant activities such as glutathione peroxidase, catalase and myeloperoxidase activities of SAEW group surpassed the total reactive oxygen species in skin. Nuclear factor erythroid-2-related-factor-2 and aryl hydrocarbon receptor were upregulated in SAEW group. Further, SAEW recruited the production of intracellular calcium and promoted its utilization for faster healing. In line, SAEW treatment decreased pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, keratinocyte chemoattractant, and tumor necrosis factor-α] in serum. Other hallmarks of wound healing, matrixmetalloproteinases (MMP)1 and MMP9 were also upregulated. Collectively, our study indicates that SAEW is effective in wound healing of hairless mice via immune-redox modulation, and heals better/faster than conventional agents.
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http://dx.doi.org/10.1248/bpb.b17-00219DOI Listing
May 2018

Effects of Combined Rocuronium and Cisatracurium in Laparoscopic Cholecystectomy.

J Lifestyle Med 2017 Jan 31;7(1):35-40. Epub 2017 Jan 31.

Department of Anesthesiology and Pain Medicine, College of Medicine, Ajou University, Suwon, Korea.

Background: Laparoscopic upper abdominal surgery can cause spontaneous respiration due to diaphragmatic stimulation and intra-abdominal CO inflation. Therefore, sufficient muscle relaxation is necessary for a safe surgical environment.

Methods: We investigated if the combination of rocuronium and cisatracurium can counteract the delayed onset of cisatracurium's action and delayed recovery of muscle relaxation and whether the dosage of rocuronium, which is metabolized hepatically, can be reduced. A total of 75 patients scheduled for laparoscopic cholecystectomy with an American Society of Anesthesiology physical status I-II, in the age range of 20-60 years, and with a 20-30 kg/m body mass index were included in the study.

Results: The patients were divided into the following groups: combination group (Group RC, rocuronium 0.3 mg/kg and cisatracurium 0.05 mg/kg), rocuronium group (Group R, rocuronium 0.6 mg/kg), and cisatracurium group (Group C, cisatracurium 0.1 mg/kg), and the onset, 25% duration, recovery index, and addition/time ratio were measured. Patients in Group RC exhibited a significantly different addition/time ratio compared with patients in the other two groups (p = 0.003).

Conclusion: During laparoscopic cholecystectomy, the 95% effective dose of rocuronium in combination with cisatracurium is expected to provide a sufficient muscle relaxant effect.
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http://dx.doi.org/10.15280/jlm.2017.7.1.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332119PMC
January 2017

Hysterectomy due to Abnormal Uterine Bleeding in a 15-year Old Girl with Rubinstein-Taybi Syndrome.

J Lifestyle Med 2016 Sep 30;6(2):76-78. Epub 2016 Sep 30.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Rubinstein-Taybi syndrome is characterized by mental retardation, atypical facial features, broad thumbs and toes, and scoliosis. Polycystic ovaries are associated with chronic anovulation and abnormal uterine bleeding. A 15-year old female patient was diagnosed with Rubinstein-Taybi Syndrome, and had prolonged abnormal uterine bleeding for 2 years, accompanied by a polycystic ovary. As she showed no improvement during hormonal therapy or medical treatment, a hysterectomy was performed to control the bleeding.
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http://dx.doi.org/10.15280/jlm.2016.6.2.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115207PMC
September 2016

Transient Oliguria during Anesthesia in Cerebral Salt Wasting Syndrome.

J Lifestyle Med 2016 Sep 30;6(2):72-75. Epub 2016 Sep 30.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Cerebral salt wasting syndrome is a hyponatremic and hypovolemic condition caused by intracranial disorders, such as head injury, subarachnoid hemorrhage, brain tumor, and brain operations. We report a case of a 5-year-old girl that had cerebral salt wasting syndrome with marked polyuria who showed transient oliguria during general anesthesia. The patient had undergone an operation for traumatic intracranial hemorrhage three months prior and has had marked polyuria and hyponatremia since then. After induction of anesthesia for cranioplasty, the patient had oliguria during surgery and then resumed polyuria in the post-operative period.
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http://dx.doi.org/10.15280/jlm.2016.6.2.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115206PMC
September 2016

Perforation of esophagus and subsequent mediastinitis following mussel shell ingestion.

J Thorac Dis 2016 Aug;8(8):E693-7

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Esophageal perforation is a very rare occurrence because accidental swallowing of foreign bodies is uncommon in adults. Thus, perforation due to swallowing of a foreign body and subsequent development of mediastinitis is rarely encountered by physicians. We experienced such a case and described an adult male patient who had perforated esophagus after accidentally swallowing a mussel shell. The patient visited our emergency department complaining of painful dysphagia for 4 days. A review of history revealed that he consumed a spicy seafood noodle soup containing mussel shells 4 days ago. Computed tomography (CT) of the chest showed the foreign body in the esophagus and pneumomediastinum was identified. We removed the mussel shell fragment using rigid esophagoscopy; explo-thoracotomy, debridement of mediastinal abscess and irrigation were performed.
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http://dx.doi.org/10.21037/jtd.2016.07.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999674PMC
August 2016

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation.

Yonsei Med J 2016 Nov;57(6):1329-38

Department of Biology, College of Natural Sciences, School of Medicine, Kangwon National University, Chuncheon, Korea.

Purpose: Peroxynitrite plays a critical role in vascular pathophysiology by increasing arginase activity and decreasing endothelial nitric oxide synthase (eNOS) activity. Therefore, the aims of this study were to investigate whether arginase inhibition and L-arginine supplement could restore peroxynitrite-induced endothelial dysfunction and determine the involved mechanism.

Materials And Methods: Human umbilical vein endothelial cells (HUVECs) were treated with SIN-1, a peroxynitrite generator, and arginase activity, nitrite/nitrate production, and expression levels of proteins were measured. eNOS activation was evaluated via Western blot and dimer blot analysis. We also tested nitric oxide (NO) and reactive oxygen species (ROS) production and performed a vascular tension assay.

Results: SIN-1 treatment increased arginase activity in a time- and dose-dependent manner and reciprocally decreased nitrite/nitrate production that was prevented by peroxynitrite scavenger in HUVECs. Furthermore, SIN-1 induced an increase in the expression level of arginase I and II, though not in eNOS protein. The decreased eNOS phosphorylation at Ser1177 and the increased at Thr495 by SIN-1 were restored with arginase inhibitor and L-arginine. The changed eNOS phosphorylation was consistent in the stability of eNOS dimers. SIN-1 decreased NO production and increased ROS generation in the aortic endothelium, all of which was reversed by arginase inhibitor or L-arginine. N(G)-Nitro-L-arginine methyl ester (L-NAME) prevented SIN-1-induced ROS generation. In the vascular tension assay, SIN-1 enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxant responses to acetylcholine that were reversed by arginase inhibition.

Conclusion: These findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions.
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http://dx.doi.org/10.3349/ymj.2016.57.6.1329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011263PMC
November 2016

Difficult Intubation in Pediatric Patient with a Large Lymphangioma at the Tongue Base.

J Lifestyle Med 2015 Mar 30;5(1):30-3. Epub 2015 Mar 30.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Lymphangioma is a congenital malformation of lymphatic system and often involves the oral cavity. When lymphangioma is located on the mouth floor and enlarges, it can compress the airway and make intubation difficult. The GlideScope(®) video laryngoscope is sometimes used in routine intubation, but is most commonly used in difficult or failed intubation. We report a pediatric patient with a difficult intubation due to a large tongue base mass. The airway was compromised due to limited intraoral space, large mass at the tongue base, and glottis distortion. Oral approach was not successful with the Macintosh laryngoscope. In this case, a rigid stylet was made to match the GlideScope(®) curve and the endo-tracheal tube was inserted through the glottis under GlideScope(®) guidance. We believe that, even in pediatric patients, a rigid stylet is necessary when intubation at a sharp posterior angulation to the trachea is difficult during GlideScope(®) approach.
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http://dx.doi.org/10.15280/jlm.2015.5.1.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608230PMC
March 2015

Suspected Anaphylactic Reaction Prior to Induction of Anesthesia.

J Lifestyle Med 2015 Mar 30;5(1):26-9. Epub 2015 Mar 30.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Although uncommon, anaphylactic reactions during surgery are very dangerous and can result in serious morbidity. Various anesthetics can trigger anaphylactic reactions, and incidents with cephalosporin antibiotics are on the rise. In the case presented, an 84-year-old woman scheduled for calcaneus fracture surgery, was injected with cefbuperazone as a prophylactic antibiotic. On the way to the operating room, before induction of anesthesia, the patient lost consciousness and showed signs of hypoxemia, and anaphylactic reaction, which included hypotension, bronchospasm, and rash. Five hours after immediate intubation and fluid resuscitation, the patient was extubated and transferred to the general ward. Eight weeks later, the skin prick test confirmed a positive reaction to cefbuperazone.
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http://dx.doi.org/10.15280/jlm.2015.5.1.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608229PMC
March 2015

Korean red ginseng water extract restores impaired endothelial function by inhibiting arginase activity in aged mice.

Korean J Physiol Pharmacol 2014 Apr 3;18(2):95-101. Epub 2014 Apr 3.

Department of Biology, Kangwon National University, Chuncheon 200-701, Korea.

Cardiovascular disease is the prime cause of morbidity and mortality and the population ages that may contribute to increase in the occurrence of cardiovascular disease. Arginase upregulation is associated with impaired endothelial function in aged vascular system and thus may contribute to cardiovascular disease. According to recent research, Korean Red Ginseng water extract (KRGE) may reduce cardiovascular disease risk by improving vascular system health. The purpose of this study was to examine mechanisms contributing to age-related vascular endothelial dysfunction and to determine whether KRGE improves these functions in aged mice. Young (10±3 weeks) and aged (55±5 weeks) male mice (C57BL/6J) were orally administered 0, 10, or 20 mg/mouse/day of KRGE for 4 weeks. Animals were sacrificed and the aortas were removed. Endothelial arginase activity, nitric oxide (NO) generation and reactive oxygen species (ROS) production, endothelial nitric oxide synthase (eNOS) coupling, vascular tension, and plasma peroxynitrite production were measured. KRGE attenuated arginase activity, restored nitric oxide (NO) generation, reduced ROS production, and enhanced eNOS coupling in aged mice. KRGE also improved vascular tension in aged vessels, as indicated by increased acetylcholine-induced vasorelaxation and improved phenylephrine-stimulated vasoconstriction. Furthermore, KRGE prevented plasma peroxynitrite formation in aged mice, indicating reduced lipid peroxidation. These results suggest KRGE exerts vasoprotective effects by inhibiting arginase activity and augmenting NO signaling and may be a useful treatment for age-dependent vascular diseases.
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http://dx.doi.org/10.4196/kjpp.2014.18.2.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994309PMC
April 2014

Effects of seasonal differences in testosterone and cortisol levels on pain responses under resting and anxiety conditions.

Yonsei Med J 2014 Jan;55(1):216-23

Department of Anesthesiology and Pain Medicine, Brain Research Group, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 220-701, Korea.

Purpose: This study investigated whether hormones and pain perception are associated with exam anxiety, and also whether exam anxiety is affected by seasonal differences in testosterone and cortisol levels.

Materials And Methods: Forty-six healthy males were recruited from a medical college. Anxiety was induced by having participants perform the Objective Structured Clinical Examination. Pressure was applied to the participants to induce pain. Pain thresholds, pain ratings, anxiety ratings, blood pressure, heart rate, salivary testosterone and cortisol levels were measured under resting and anxiety conditions in the spring and summer. Data were collected from 46 participants during the spring (n=25) and summer (n=21).

Results: Pain thresholds and testosterone levels were significantly lower under anxiety than at rest for all participants (n=46), while cortisol levels, pain ratings, and anxiety ratings were significantly higher under anxiety than at rest. In the spring (n=25), testosterone levels were significantly higher at rest than under anxiety, while there was no difference in cortisol levels between resting and anxiety conditions. In the summer (n=21), cortisol levels were significantly higher under anxiety than at rest, while there was no difference in testosterone levels between resting and anxiety conditions. There were no significant seasonal differences in pain and anxiety ratings and pain threshold.

Conclusion: These results indicate that seasonal differences in testosterone and cortisol levels under anxiety and at rest may affect pain responses. These results also suggest that acute clinical pain may be relieved by managing anxiety that is related to a decrease of testosterone in spring and a large increase of cortisol in summer.
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http://dx.doi.org/10.3349/ymj.2014.55.1.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874911PMC
January 2014

A failure of internal jugular vein catheterization caused by the internal jugular vein occlusion.

Korean J Anesthesiol 2013 Oct;65(4):361-2

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

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http://dx.doi.org/10.4097/kjae.2013.65.4.361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822034PMC
October 2013

Change of respiratory mechanics at different intra-abdominal pressures and position change during laparoscopic surgery.

Korean J Anesthesiol 2013 Jun;64(6):560-1

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

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http://dx.doi.org/10.4097/kjae.2013.64.6.560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695261PMC
June 2013

The effects of desflurane and sevoflurane on the intraocular pressure associated with endotracheal intubation in pediatric ophthalmic surgery.

Korean J Anesthesiol 2013 Feb 15;64(2):117-21. Epub 2013 Feb 15.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Background: For ophthalmic surgery anesthesia, it is vital that intraocular pressure (IOP) is controlled. Most anesthetic drugs affect IOP dose-dependently, and inhalational anesthetics dose-dependently decrease IOP. In this study, we compared the effects of desflurane and sevoflurane on IOP and hemodynamics in pediatric ophthalmic surgery.

Methods: Thirty eight pediatric patients from the age of 6 to 15 years, who were scheduled for strabismus surgery and entropion surgery, were randomized to be administered desflurane (group D, n = 19) or sevoflurane (group S, n = 19). IOPs and hemodynamic parameters were measured before induction of anesthesia (B), after induction but immediately before intubation (AI), 1 min after intubation (T1), 3 min after intubation (T3), and 5 min after intubation (T5).

Results: The mean arterial pressure (MAP) at T1 and heart rates (HRs) at T1 and T3 were significantly higher in group D than those in group S. There was no significant difference between the groups in IOP, cardiac index (CI) and stroke index (SI). There was a significant difference within the group in IOP, SI, MAP and HR. There was no significant difference within the group in CI.

Conclusions: There was no significant difference between the groups in IOP and hemodynamic parameters. The two anesthetic agents maintained IOP and hemodynamic parameters in the normal range during anesthetic induction.
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http://dx.doi.org/10.4097/kjae.2013.64.2.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581779PMC
February 2013

Thyroid storm during induction of anesthesia.

Korean J Anesthesiol 2012 Nov 16;63(5):477-8. Epub 2012 Nov 16.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

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http://dx.doi.org/10.4097/kjae.2012.63.5.477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506864PMC
November 2012

A comparison of the influence of 2.7% sorbitol-0.54% mannitol and 5% glucose irrigating fluids on plasma serum physiology during hysteroscopic procedures.

Korean J Anesthesiol 2011 Nov 23;61(5):394-8. Epub 2011 Nov 23.

Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.

Background: 2.7% sorbitol-0.54% mannitol has been selected as an alternative irrigating fluid during endoscopic surgery for its theoretical advantages. We compared the influence of 2.7% sorbitol-0.54% mannitol (Urosol™, CJ Pharma, Seoul, Korea) and 5% glucose as an irrigating solution for hysteroscopic myomectomy & polypectomy in the occurrence of associated complications.

Methods: Thirty patients scheduled for a hysteroscopic operation were included in a prospective randomized trial comparing 2.7% sorbitol-0.54% mannitol solution (Group S, n = 15) and 5% glucose (Group G, n = 15) as an irrigating fluid. We recorded the amount of the irrigating fluids, the amount of fluid intake, and the duration of the procedure. Serum sodium, chloride, potassium, glucose values, and serum osmolality were measured before (just after the induction, T1), during (when 2 L of irrigation fluid was infused, T2), and after (1 h after the end of the operation, T3) the hysteroscopic procedure.

Results: The mean volume of absorbed irrigating fluid was 185.0 ± 73.5 ml in Group G and 175.4 ± 50.5 ml in Group S. Transient hyperglycemia occurred in one patient of Group G. No differences were found in the intraoperative and postoperative levels of serum sodium, potassium, chloride, glucose and osmolality in both groups.

Conclusions: There was no clinical evidence of hyponatremic hypoosmolality in any of the patients. We found no difference between 2.7% sorbitol-0.54% mannitol and 5% glucose as an irrigating fluid for hysteroscopic procedures with mild to moderate irrigant absorption.
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http://dx.doi.org/10.4097/kjae.2011.61.5.394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229018PMC
November 2011

Endothelial arginase II and atherosclerosis.

Korean J Anesthesiol 2011 Jul 17;61(1):3-11. Epub 2011 Jul 17.

Division of Biology, Kangwon National University, Chuncheon, Korea.

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in developed countries. While it is a complex condition resulting from numerous genetic and environmental factors, it is well recognized that oxidized low-density lipoprotein produces pro-atherogenic effects in endothelial cells (ECs) by inducing the expression of adhesion molecules, stimulating EC apoptosis, inducing superoxide anion formation and impairing protective endothelial nitric oxide (NO) formation. Emerging evidence suggests that the enzyme arginase reciprocally regulates NO synthase and NO production by competing for the common substrate L-arginine. As oxidized LDL (OxLDL) results in arginase activation/upregulation, it appears to be an important contributor to endothelial dysfunction by a mechanism that involves substrate limitation for endothelial NO synthase (eNOS) and NO synthesis. Additionally, arginase enhances production of reactive oxygen species by eNOS. Arginase inhibition in hypercholesterolemic (ApoE(-/-)) mice or arginase II deletion (ArgII(-/-)) mice restores endothelial vasorelaxant function, reduces vascular stiffness and markedly reduces atherosclerotic plaque burden. Furthermore, arginase activation contributes to vascular changes including polyamine-dependent vascular smooth muscle cell proliferation and collagen synthesis. Collectively, arginase may play a key role in the prevention and treatment of atherosclerotic vascular disease.
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http://dx.doi.org/10.4097/kjae.2011.61.1.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155133PMC
July 2011

Arginase Inhibition by Ethylacetate Extract of Caesalpinia sappan Lignum Contributes to Activation of Endothelial Nitric Oxide Synthase.

Korean J Physiol Pharmacol 2011 Jun 30;15(3):123-8. Epub 2011 Jun 30.

Department of Biology, Kangwon National University, Chuncheon 200-701, Korea.

Caesalpinia sappan (C. sappan) is a medicinal plant used for promoting blood circulation and removing stasis. During a screening procedure on medicinal plants, the ethylacetate extract of the lignum of C. sappan (CLE) showed inhibitory activity on arginase which has recently been reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. CLE inhibited arginase II activity prepared from kidney lysate in a dose-dependent manner. In HUVECs, inhibition of arginase activity by CLE reciprocally increased NOx production through enhancement of eNOS dimer stability without any significant changes in the protein levels of eNOS and arginase II expression. Furthermore, CLE-dependent arginase inhibition resulted in increase of NO generation and decrease of superoxide production on endothelium of isolated mice aorta. These results indicate that CLE augments NO production on endothelium through inhibition of arginase activity, and may imply their usefulness for the treatment of cardiovascular diseases associated with endothelial dysfunction.
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http://dx.doi.org/10.4196/kjpp.2011.15.3.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154375PMC
June 2011

HZE ⁵⁶Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase.

Radiat Res 2011 Oct 25;176(4):474-85. Epub 2011 Jul 25.

Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.
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http://dx.doi.org/10.1667/rr2598.1DOI Listing
October 2011

Native low-density lipoprotein-dependent interleukin-8 production through pertussis toxin-sensitive G-protein coupled receptors and hydrogen peroxide generation contributes to migration of human aortic smooth muscle cells.

Yonsei Med J 2011 May;52(3):413-9

Department of Biology, Kangwon National University, Chuncheon 200-701, Korea.

Purpose: Stimulation of human aortic smooth muscle cells (hAoSMCs) with native low-density lipoprotein (nLDL) induced the production of interleukin-8 (IL-8) that is involved in the pathogenesis of cardiovascular diseases. However, the process of signal transduction of nLDL was currently uncharacterized. Therefore, the aim of this study was to investigate the signal transduction pathway of nLDL-dependent IL-8 production and the effect of IL-8 on hAoSMCs migration.

Materials And Methods: nLDL was prepared by ultracentrifugation with density-adjusted human serum of normocholesterolemia. In hAoSMCs, IL-8 secreted to medium was measured using ELISA assay, and Western blot analysis was performed to detect p38 MAPK activation as a key regulator of IL-8 production. nLDL-dependent H₂O₂ generation was determined by microscopic analysis using 2',7'-dichlorofluoroscein diacetate (DCF-DA). IL-8-induced migration of hAoSMCs was evaluated by counting the cell numbers moved to lower chamber using Transwell plates.

Results: nLDL-induced IL-8 production was completely blocked by preincubation of hAoSMCs with pertussis toxin (PTX), which inhibited nLDL-dependent p38 MAPK phosphorylation. PTX-sensitive G-protein coupled receptor was responsible for nLDL-dependent H₂O₂ generation that was abrogated with preincubation of the cells with of polyethylene glycol-conjugated catalase (PEG-Cat). Pretreatment of PEG-Cat prevented nLDL-induced p38 MAPK phosphorylation and IL-8 production, which was partly mimicked by treatment with exogenous H₂O₂2. Finally, IL-8 increased hAoSMCs migration that was completely blocked by incubation with IL-8 neutralizing antibody.

Conclusion: PTX-sensitive G-protein coupled receptor-dependent H₂O₂ generation by nLDL plays a critical role in IL-8 production in hAoSMC, and IL-8 may contribute to atherogenesis through increased migration of hAoSMCs.
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http://dx.doi.org/10.3349/ymj.2011.52.3.413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101039PMC
May 2011

Stress-induced cardiomyopathy after general anesthesia for total gastrectomy -A case report-.

Korean J Anesthesiol 2010 Mar 29;58(3):299-303. Epub 2010 Mar 29.

Department of Anesthesiology and Pain Medicine, Yonsei Unversity Wonju College of Medicine, Wonju, Korea.

Stress-induced cardiomyopathy, which is also known as takotsubo cardiomyopathy, is a cardiac syndrome of a transient, reversible left ventricular dysfunction that is caused by emotional and/or physical stress and surgery. Its clinical manifestations are similar to those of myocardial ischemia without a coronary artery lesion. Stress-induced cardiomyopathy is more common in middle-aged women, and the prognosis is favorable. We report the case of a 50-year-old female patient who underwent a total gastrectomy and developed stress-induced cardiomyopathy after surgery.
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http://dx.doi.org/10.4097/kjae.2010.58.3.299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872848PMC
March 2010

Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta.

J Appl Physiol (1985) 2010 May 18;108(5):1250-8. Epub 2010 Feb 18.

Department of Biomedical Engineering, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Tower 711, Baltimore, MD 21287, USA.

Radiation exposure is associated with the development of various cardiovascular diseases. Although irradiation is known to cause elevated oxidant stress and chronic inflammation, both of which are detrimental to vascular function, the molecular mechanisms remain incompletely understood. We previously demonstrated that radiation causes endothelial dysfunction and increased vascular stiffness by xanthine oxidase (XO) activation. In this study, we investigated whether dietary inhibition of XO protects against radiation-induced vascular injury. We exposed 4-mo-old rats to a single dose of 0 or 5 Gy gamma radiation. These rats received normal drinking water or water containing 1 mM oxypurinol, an XO inhibitor. We measured XO activity and superoxide production in rat aorta and demonstrated that both were significantly elevated 2 wk after radiation exposure. However, oxypurinol treatment in irradiated rats prevented aortic XO activation and superoxide elevation. We next investigated endothelial function through fluorescent measurement of nitric oxide (NO) and vascular tension dose responses. Radiation reduced endothelium-dependent NO production in rat aorta. Similarly, endothelium-dependent vasorelaxation in the aorta of irradiated rats was significantly attenuated compared with the control group. Dietary XO inhibition maintained NO production at control levels and prevented the development of endothelial dysfunction. Furthermore, pulse wave velocity, a measure of vascular stiffness, increased by 1 day postirradiation and remained elevated 2 wk after irradiation, despite unchanged blood pressures. In oxypurinol-treated rats, pulse wave velocities remained unchanged from baseline throughout the experiment, signifying preserved vascular health. These findings demonstrate that XO inhibition can offer protection from radiation-induced endothelial dysfunction and cardiovascular complications.
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http://dx.doi.org/10.1152/japplphysiol.00946.2009DOI Listing
May 2010
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