Ye, Byeong Hyeok
(Department of Pharmacology, School of Medicine, Pusan National University)
,
Kim, Eun Jung
(Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University)
,
Baek, Seung Eun
(Department of Pharmacology, School of Medicine, Pusan National University)
,
Choi, Young Whan
(College of Natural Resources & Life Sciences, Pusan National University)
,
Park, So Youn
(Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University)
,
Kim, Chi Dae
(Department of Pharmacology, School of Medicine, Pusan National University)
${\alpha}$-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms, but the mechanism responsible for this activity has not been determined. To determine the role played by ICB on the...
${\alpha}$-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms, but the mechanism responsible for this activity has not been determined. To determine the role played by ICB on the regulation of vascular tone, we investigated the inhibitory effects of ICB on vascular contractile responses by adrenergic ${\alpha}$-receptor agonists. In addition, we investigated the role on myosin light chain (MLC) phosphorylation and cytosolic calcium concentration in vascular smooth muscle cells (VSMC). In aortic rings isolated from C57BL/6J mice, ICB significantly attenuated the contraction induced by phenylephrine (PE) and norepinephrine (NE), whereas ICB had no effects on KCl (60 mM)-induced contraction. In vasculatures precontracted with PE, ICB caused marked relaxation of aortic rings with or without endothelium, suggesting a direct effect on VSMC. In cultured rat VSMC, PE or NE increased MLC phosphorylation and increased cytosolic calcium levels. Both of these effects were significantly suppressed by ICB. In conclusion, our results showed that ICB regulated vascular tone by inhibiting MLC phosphorylation and calcium flux into VSMC, and suggest that ICB has anti-hypertensive properties and therapeutic potential for cardiovascular disorders related to vascular hypertension.
${\alpha}$-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms, but the mechanism responsible for this activity has not been determined. To determine the role played by ICB on the regulation of vascular tone, we investigated the inhibitory effects of ICB on vascular contractile responses by adrenergic ${\alpha}$-receptor agonists. In addition, we investigated the role on myosin light chain (MLC) phosphorylation and cytosolic calcium concentration in vascular smooth muscle cells (VSMC). In aortic rings isolated from C57BL/6J mice, ICB significantly attenuated the contraction induced by phenylephrine (PE) and norepinephrine (NE), whereas ICB had no effects on KCl (60 mM)-induced contraction. In vasculatures precontracted with PE, ICB caused marked relaxation of aortic rings with or without endothelium, suggesting a direct effect on VSMC. In cultured rat VSMC, PE or NE increased MLC phosphorylation and increased cytosolic calcium levels. Both of these effects were significantly suppressed by ICB. In conclusion, our results showed that ICB regulated vascular tone by inhibiting MLC phosphorylation and calcium flux into VSMC, and suggest that ICB has anti-hypertensive properties and therapeutic potential for cardiovascular disorders related to vascular hypertension.
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제안 방법
In this study, aortic rings were incubated with various concentrations of ICB for 10 min, and then phenylephrine (PE) or norepinephrine (NE) was added to induce transient vasoconstriction. The vasodilatory potency of ICB was studied using cumulative additions of ICB at concentrations of 1–10 μg/ml.
To examine whether ICB attenuates transient increases in cytosolic Ca2+ induced by PE or NE, rat VSMC were used in this study. When PE (1 μM) or NE (0.
To further investigate the involvement of vascular endothelium on the vascular action of ICB, the vasorelaxing effects of ICB were examined in endothelium-intact or -denuded aortic preparations pre-contracted by PE. As shown in Fig.
대상 데이터
Phenylephrine hydrochloride (PE), acetylcholine chloride, and EGTA were purchased from Sigma-Aldrich (St. Louis, MO). MTT working solution was from EZ-Cytox (Daeil Laboratories, Seoul), and antibodies for MLC (sc-12896), p-MLC (sc-19848, sc-293109), and anti-β-actin (sc-47778) were from Santa Cruz Biotechnology.
85-23, 2011 revision), and all experimental protocols were approved by the Pusan National University Institutional Animal Care and Use Committee. Wildtype control mice (C57BL/6J) were purchased from Jackson Laboratories. All animals were housed in an air-conditioned room at 22–25°C and kept under a 12-h light/dark cycle.
데이터처리
Results are presented as means±S.E.M. One-way analysis of variance followed by Tukey’s multiple comparison test was used to determine the significances of intergroup differences.
후속연구
Thus, it was suggested that ICB regulated vascular tone by inhibiting MLC phosphorylation and calcium flux. However, further studies are required to clarify the detail signaling mechanism, in which ICB regulates MLC phosphorylation.
참고문헌 (40)
1 Flack JM Oparil S Pratt JH Roniker B Garthwaite S Kleiman JH Yang Y Krause SL Workman D Saunders E Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients J Am Coll Cardiol 2003 41 1148 1155 12679215
2 Ohanian J Ohanian V Lipid second messenger regulation: the role of diacylglycerol kinases and their relevance to hypertension J Hum Hypertens 2001 15 93 98 11317187
3 Touyz RM He G Wu XH Park JB Mabrouk ME Schiffrin EL Src is an important mediator of extracellular signal-regulated kinase 1/2-dependent growth signaling by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients Hypertension 2001 38 56 64 11463760
4 Staiculescu MC Galinanes EL Zhao G Ulloa U Jin M Beig MI Meininger GA Martinez-Lemus LA Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling Cardiovasc Res 2013 98 428 436 23417038
7 Kim JI High fat diet confers vascular hyper-contractility against angiotensin II through upregulation of MLCK and CPI-17 Korean J Physiol Pharmacol 2017 21 99 106 28066146
8 Somlyo AP Somlyo AV Ca 2+ sensitivity of smooth muscle and non-muscle myosin II: modulated by G proteins, kinases, and myosin phosphatase Physiol Rev 2003 83 1325 1358 14506307
12 Gong MC Cohen P Kitazawa T Ikebe M Masuo M Somlyo AP Somlyo AV Myosin light chain phosphatase activities and the effects of phosphatase inhibitors in tonic and phasic smooth muscle J Biol Chem 1992 267 14662 14668 1321813
13 Mu Y Zhang J Zhang S Zhou HH Toma D Ren S Huang L Yaramus M Baum A Venkataramanan R Xie W Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats J Pharmacol Exp Ther 2006 316 1369 1377 16267138
14 Huang SX Li RT Liu JP Lu Y Chang Y Lei C Xiao WL Yang LB Zheng QT Sun HD Isolation and characterization of biogenetically related highly oxygenated nortriterpenoids from Schisandra chinensis Org Lett 2007 9 2079 2082 17480084
15 Rhyu MR Kim EY Yoon BK Lee YJ Chen SN Aqueous extract of Schizandra chinensis fruit causes endothelium-dependent and -independent relaxation of isolated rat thoracic aorta Phytomedicine 2006 13 651 657 16704926
16 Park JY Shin HK Lee YJ Choi YW Bae SS Kim CD The mechanism of vasorelaxation induced by Schisandra chinensis extract in rat thoracic aorta J Ethnopharmacol 2009 121 69 73 18983904
17 Park JY Choi YW Yun JW Bae JU Seo KW Lee SJ Park SY Kim CD Gomisin J from Schisandra chinensis induces vascular relaxation via activation of endothelial nitric oxide synthase Vascul Pharmacol 2012 57 124 130 22728282
18 Lee YJ Shim JW Lee YJ Park YH Lee HY Kim SD Choi YW Bae YS Identification of a novel compound that stimulates intracellular calcium increase and CXCL8 production in human neutrophils from Schisandra chinensis Biochem Biophys Res Commun 2009 379 928 932 19138665
20 Turbedsky K Pollard TD Bresnick AR A subset of protein kinase C phosphorylation sites on the myosin II regulatory light chain inhibits phosphorylation by myosin light chain kinase Biochemistry 1997 36 2063 2067 9047304
21 Chen K Li C Recent advances in studies on traditional Chinese anti-aging material medica J Tradit Chin Med 1993 13 223 226 8246603
22 You JS Pan TL Hou YC Schisandra chinensis protects against adriamycin-induced cardiotoxicity in rats Chang Gung Med J 2006 29 63 70 16642728
23 Choi YW Takamatsu S Khan SI Srinivas PV Ferreira D Zhao J Khan IA Schisandrene, a dibenzocyclooctadiene lignan from Schisandra chinensis: structure-antioxidant activity relationships of dibenzocyclooctadiene lignans. J Nat Prod 2006 69 356 359 16562834
25 Park SY Park SJ Park NJ Joo WH Lee SJ Choi YW α-Isocubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation Neurosci Lett 2013 555 143 148 24090820
26 Choi YW Kim HJ Park SS Chung JH Lee HW Oh SO Kim BS Kim JB Chung HY Yu BP Kim CD Yoon S Inhibition of endothelial cell adhesion by the new anti-inflammatory agent alpha-isocubebene Vascul Pharmacol 2009 51 215 224 19539051
27 Park SY Park TG Lee SJ Bae YS Ko MJ Choi YW α-Iso-cubebenol inhibits inflammation-mediated neurotoxicity and amyloid beta 1-42 fibril-induced microglial activation J Pharm Pharmacol 2014 66 93 105 24138316
28 Park SY Choi YH Park G Choi YW Neuroprotective effects of α-iso-cubebenol on glutamate-induced neurotoxicity Environ Toxicol Pharmacol 2015 40 549 556 26322719
29 Jang MA Lee SJ Baek SE Park SY Choi YW Kim CD α-Iso-Cubebene inhibits PDGF-induced vascular smooth muscle cell proliferation by suppressing osteopontin expression PLoS One 2017 12 e0170699 28114367
30 Safar ME Balkau B Lange C Protogerou AD Czemichow S Blacher J Levy BI Smulyan H Hypertension and vascular dynamics in men and women with metabolic syndrome J Am Coll Cardiol 2013 61 12 19 23287369
31 Touyz RM Schiffrin EL Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P) H oxidase-sensitive pathways J Hypertens 2001 19 1245 1254 11446714
33 Sun N Hong T Zhang R Yang X The effects of verapamil SR and bisoprolol on reducing the sympathetic nervous system's activity Hypertens Res 2000 23 537 540 11016810
34 Zheng C Lo CY Meng Z Li Z Zhong M Zhang P Lu J Yang Z Yan F Zhang Y Huang Y Yao X Gastrodin inhibits store-operated Ca 2+ entry and alleviates cardiac hypertrophy Front Pharmacol 2017 8 222 28487655
35 Meisheri KD Hwang O van Breemen C Evidence for two separated Ca 2+ pathways in smooth muscle plasmalemma J Membr Biol 1981 59 19 25 7241573
36 Eto K Ohya Y Nakamura Y Abe I Fujishima M Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle Eur J Pharmacol 2001 423 1 7 11438300
37 Shibata K Sakai H Huang Q Kamata H Chiba Y Misawa M Ikebe R Ikebe M Rac1 regulates myosin II phosphorylation through regulation of myosin light chain phosphatase J Cell Physiol 2015 230 1352 1364 25502873
38 Kokubo Y Okamura T Watanabe M Higashiyama A Ono Y Miyamoto Y Furukawa Y Kamide K Kawanishi K Okayama A Yoshimasa Y The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita Study Hypertens Res 2010 33 1238 1243 20927111
39 Seok YM Cho HJ Cha BY Woo JT Kim IK Honokiol attenuates vascular contraction through the inhibition of the RhoA/Rhokinase signalling pathway in rat aortic rings J Pharm Pharmacol 2011 63 1244 1251 21827498
40 Kang G Lee YR Joo HK Park MS Kim CS Choi S Jeon BH Trichostatin A modulates angiotensin II-induced vasoconstriction and blood pressure via inhibition of p66shc activation Korean J Physiol Pharmacol 2015 19 467 472 26330760
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