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Resveratrol Is an Arginase Inhibitor Contributing to Vascular Smooth Muscle Cell Vasoconstriction Via Increasing Cytosolic Calcium

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Resveratrol Is an Arginase Inhibitor Contributing to Vascular Smooth Muscle Cell Vasoconstriction Via Increasing Cytosolic Calcium MOLECULAR MEDICINE REPORTS 19: 3767-3774, 2019 Resveratrol is an arginase inhibitor contributing to vascular smooth muscle cell vasoconstriction via increasing cytosolic calcium CHANG IK CHOI1*, BON HYEOCK KOO2*, DONGEUI HONG1, HYUNG JOO KWON3, KWANG LAE HOE4, MOO HO WON5, YOUNG MYEONG KIM6, HYUN KYO LIM1 and SUNGWOO RYOO2 1Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon 26426; 2Department of Biology, Kangwon National University, Chuncheon, Gangwon 24341; 3Department of Microbiology, School of Medicine, Hallym University, Chuncheon, Gangwon 24252; 4New Drug Discovery and Development, Chungnam National University, Daejeon 34134; Departments of 5Neurobiology, and 6Molecular and Cellular Biochemistry, and Neurobiology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea Received November 15, 2018; Accepted February 28, 2019 DOI: 10.3892/mmr.2019.10035 Abstract. The contractility of vascular smooth muscle cells using phenylephrine (PE), were significantly enhanced in the (VSMCs) controls the lumen diameter of vessels, thus serving RSV- and L-Arg-treated vessels. Therefore, although arginase a role in regulating blood pressure and organ blood flow. inhibition has exhibited beneficial effects in various diseases, Although arginases are known to have numerous effects in the care is required when considering administration of an argi- biological activities of VSMCs, the effects of arginase II on the nase inhibitor to patients with vessels endothelial dysfunction constriction of VSMCs has not yet been investigated. When as RSV can induce vessel contraction. conducting a natural products screen for an inhibitor against arginase, the present study identified that a relatively high Introduction concentration of resveratrol (RSV) exhibited arginase inhibi- tory activity. Therefore, the present study investigated whether Arginase is the enzyme that functions in the last step of the RSV could regulate VSMCs contractions and the underlying urea cycle to hydrolyzes L-arginine (L-Arg) to L-ornithine mechanism. Arginase inhibition by RSV led to an increase in and urea. The arginase isoforms, arginase I and II, are encoded the concentration of the substrate L-Arg and an accompanying by distinct genes, show 60% sequence homology, and exhibit increase in the cytosol Ca2+ concentration [(Ca2+)c] in VSMCs. different tissue distribution and subcellular localization The increased [Ca2+]c induced by RSV and L-Arg treatments patterns. Arginase I is a cytosolic enzyme that is abundantly resulted in CaMKII-dependent MLC20 phosphorylation. The expressed in the liver, whereas arginase II is a mitochondrial effects of RSV on VSMCs were maintained even when VSMCs protein that is predominantly expressed in the kidney (1,2). were pre-treated with sirtinol, an inhibitor of Sirt proteins. In addition to its primary function in the urea cycle, arginase In a vascular tension assay with de-endothelialized aortic exhibits various biological activities in vascular smooth vessels, vasoconstrictor responses, which were measured muscle cells (VSMCs). In VSMCs of the rat carotid artery, inhibition or knockdown of arginase I led to attenuated medial and neointimal DNA synthesis and neointima formation (3). In mouse VSMCs, arginase II is involved in cell senescence and apoptosis (4). In our previous studies, we demonstrated that Correspondence to: Professor Sungwoo Ryoo, Department the proliferation of rat VSMCs, induced by the inflammatory of Biology, Kangwon National University, Kangwondae-gil 1, Chuncheon, Gangwon 24341, Republic of Korea cytokine, interleukin-1β, was suppressed by inhibition of argi- E-mail: [email protected] nase in a cGMP-dependent manner (5). Inhibition of arginase II also inhibited Ca2+ uptake into the mitochondria of native Professor Hyun Kyo Lim, Department of Anesthesiology and low-density lipoprotein-stimulated human aortic smooth Pain Medicine, Yonsei University Wonju College of Medicine, muscle cells, thus arginase II activity may regulate Ca2+ 20 Ilsan-ro, Wonju, Gangwon 26426, Republic of Korea E-mail: [email protected] levels in the cytosol and the mitochondria (6). Furthermore, we recently reported that inhibition of arginase II activated *Contributed equally endothelial nitric oxide synthase by increasing the cytosolic Ca2+ level [(Ca2+)] in a p32-dependent manner (7). Key words: arginase inhibition, cytosolic Ca2+, resveratrol, vascular The modulation of smooth muscle tone by various factors smooth muscle cells, vasoconstriction in the vasculature plays a role in the control of lumen diam- eter, which associated with blood pressure and organ blood flow (8-10). All smooth muscle cells produce force and 3768 CHOI et al: ROLE OF RESVERATROL IN VSMC CONSTRICTION contraction through cross-bridge cycling between actin and as previously described (19) with minor modifications. Briefly, myosin filaments. The contraction response is the result of the rat were anesthetized with isoflurane, aortas were stripped myosin-light chain kinase (MLCK) and myosin-light chain and cut into 2 mm pieces that were treated with 1 mg/ml of phosphatase (MLCP) activation. In VSMCs, this process is type II collagenase (Invitrogen; Thermo Fisher Scientific, Inc., dependent on the Ca2+‑mediated change in the myosin fila- Waltham, MA, USA) for 1 h to remove the endothelial cells, ments (9). Increased intracellular Ca2+ is a primary target of and then the cells were washed with the culture medum. The the EF-hand Ca2+-binding protein calmodulin, and then the de-endothelialized pieces of aorta were incubated with culture Ca2+/calmodulin complex activates MLCK via Ca2+/calmod- medium in a gelatin (0.1%)-coated culture dish for approxi- ulin-dependent protein kinase II (CaMKII) phosphorylation. mately 10 d. The VSMCs cultures were confirmed to be >95% Contraction can also occur independent of Ca2+ through the pure by immunocytochemical staining for α-smooth muscle activation of the RhoA/Rho kinase pathway, which leads to actin. VSMCs that were passaged 2-5 times were used in the MLCP inactivation and maintenance of the contraction (11). subsequent experiments. The culture medium consisted of Because the contractile activity of VSMCs plays an impor- Dulbecco's modified Eagle's medium (DMEM) supplemented tant role in the regulation of vascular tone in the vessels, its with 10% fetal bovine serum (FBS), 0.5X smooth muscle dysregulation can result in endothelial dysfunction leading growth supplement (Cascade Biologics, Portland, OR, USA), to cardiovascular diseases. Therefore, identifying natural 100 U/ml penicillin, 100 µg/ml streptomycin, 8 mM HEPES, compounds that can effectively inhibit arginase to control this and 2 mM glutamine. The VSMCs were cultured at 37˚C in a contractile activity would offer a new strategy for the treatment humidified 5% CO2 incubator. and prevention of vascular conditions. Resveratrol (RSV) is a small polyphenol found in grapes, berries, and peanuts, and Arginase activity assay and intracellular L‑Arg quantification. is considered to protect against cardiovascular diseases by Arginase activity was determined by quantifying the urea reducing platelet aggregation, low-density lipoprotein oxida- generated from L-Arg substrate as previously described (20). tion, prostagladin synthesis, and endothelial cells activation by Intracellular concentrations of L-Arg were determined tumor necrosis factor-α, as well as by activating and inducing using high-performance liquid chromatography (HPLC) endothelial nitric oxide synthase (12-14). RSV has been known with pre-column derivatization with o-phthalaldehyde to activate to SirT proteins that post-translationally regulate (OPA) according to a modification of previously published protein activity by deacetylation, and RSV-dependent activa- methods (21). Briefly, L-Arg (100 µmol/l) and polyamine tion of SirT has showed a marked reduction in the signs of (30 µmol/l/each) were added to the cell lysate (0.1 mmol/l) as aging. On the other hand, inhibitors of SirT, such as sirtinol and internal standard. The samples were extracted on solid-phase splitomicin, were proposed to treat cancer and human immu- extraction cartridges (CBA Bond elute, Varian), with a recovery nodeficiency virus infection (15). Moreover, RSV was found to rate of 87.5±3.9% to L-Arg. The eluates were dried over prevent angiotensin II-stimulated hypertrophy (16) and NADPH nitrogen and resuspended in double-distilled water for HPLC oxidase-dependent proliferation (17), as well as to induce differ- analysis. HPLC was performed on a computer-controlled entiation to a contractile phenotype in VSMCs (18). However, Waters chromatography system (M600E) consisting of an the effect of RSV on the regulation of VSMCs contractility automatic injector (M7725i, Waters Co.) and a fluorescence remains unknown. We hypothesized that RSV regulates VSMCs detector (FP-1520, Jasco Co.). Samples were incubated for contractions by inhibiting arginase. To test this hypothesis, we 1 min with OPA reagent (5.4 mg/ml OPA in borate buffer, treated rat VSMCs with RSV and determined the effects on pH 8.4, with 0.4% 2-mercaptoethanol) before automatic injec- arginase activity and [Ca2+]c, as well as the effecs on contrac- tion into the HPLC system. The OPA derivatives of L-Arg tion by evaluating the change in CaMKII-dependent MLC20 and polyamine were separated on a 150x4.6 mm-5 µm Zorbax phosphorylation. We further determined the effects of RSV Eclipse XDB‑C18 column with the fluorescence
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