저온 노출된 혈관 세포 내 RhoA 단백질 활성화에 대한 십전대보탕의 억제 효과 = Mitigative Effect of Sipjeondaebo-tang on RhoA Activation in Cold-Exposed Vascular Cells

다국어 초록 (Multilingual Abstract)

Objective: To investigate the vasodilatory effect of Sipjeondaebo-tang by inhibiting RhoA activity in vascular cells during cold exposure.
Methods: Human vascular endothelial cells and pericytes were pretreated with Sipjeondaebo-tang for 30 min, followed by incubation at 37 ℃ (control) or 25 ℃ (cold exposure) for 30 min. Activation of endothelin-1-mediated RhoA in pericytes was assessed by pretreating the cells with Sipjeondaebo-tang for 30 min, followed by incubation with endothelin-1 at 37 ℃ for 30 min. Western blotting was performed to measure the expression of active RhoA. Endothelin-1 and nitric oxide release from endothelial cells was examined with enzyme-linked immunosorbent assay kits. The formation of stress fibers and focal adhesion complexes was analyzed by immunocytochemistry.
Results: Cold treatment activated RhoA in both pericytes and vascular endothelial cells, whereas Sipjeondaebo-tang treatment inhibited this activation. Sipjeondaebo-tang treatment also reversed the cold-mediated production of endothelin-1 and nitric oxide. Cold exposure promoted the formation of stress fibers and focal adhesion complexes by increasing the expression of phospho-focal adhesion complex kinase, whereas Sipjeondaebo-tang treatment suppressed this response.
Conclusions: These findings suggested that Sipjeondaebo-tang inhibits cold-induced RhoA activation and its related pathway components, including endothelin-1 and nitric oxide, in vascular cells. Therefore, Sipjeondaebo-tang could be beneficial for the treatment of Raynaud’s phenomenon.

참고문헌 (Reference)

1 송효원, "십전대보탕의 활용에 대한 문헌적 고찰" 4 (4): 153-172, 1996

2 "식품의약품안전처 인터넷 사이트"

3 명정호, "가미십전대보탕의 RAW 264.7 세포에서 항산화 및 항염증 효과" 한국식품영양과학회 46 (46): 1271-1277, 2017

4 Momotani K, "p63RhoGEF Couples G(alpha q/11)-Mediated Signaling to Ca2+Sensitization of Vascular Smooth Muscle Contractility" 109 (109): 993-1002, 2011

5 Yoo MY, "Vasorelaxant effect of the rootbark extract of Paeonia moutan on isolated rat thoracic aorta" 72 (72): 1338-1341, 2006

6 Zhao Y, "Vasorelaxant effect of formononetin in the rat thoracic aorta and its mechanisms" 14 (14): 46-54, 2012

7 Kang YH, "Vasodilatory effects of cinnamic acid via the nitric oxide- cGMP-PKG pathway in rat thoracic aorta" 27 (27): 205-211, 2013

8 Xue YL, "Vasodilatory effects of cinnamaldehyde and its mechanism of action in the rat aorta" 7 : 273-280, 2011

9 Barman SA, "Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C" 293 (293): L472-L479, 2007

10 Wu YJ, "Vascular response of Raynaud's phenomenon to nifedipine or herbal medication(duhuo-tisheng tang with danggui-sini tang) : a preliminary study" 31 (31): 492-502, 2008

11 Tousoulis D, "The role of nitric oxide on endothelial function" 10 (10): 4-18, 2012

12 Rychlik-Golema W, "The role of endothelin-1 and selected cytokines in the pathogenesis of Raynaud's phenomenon associated with systemic connective tissue diseases" 25 (25): 221-227, 2006

13 Yao L, "The role of RhoA/Rho kinase pathway in endothelial dysfunction" 1 (1): 165-170, 2010

14 Malenfant D, "The efficacy of complementary and alternative medicine in the treatment of Raynaud's phenomenon : a literature review and meta-analysis" 48 (48): 791-795, 2009

15 Lee YM, "Sipjeondaebo-Tang, a Traditional Herbal Formula, Inhibits Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy" 234 (234): 229-236, 2014

16 Zamora MR, "Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon" 336 (336): 1144-1147, 1990

17 Yamakawa J, "Role of Kampo medicine in integrative cancer therapy" 2013 : 570848-, 2013

18 Bailey SR, "Rho kinase mediates cold-induced constriction of cutaneous arteries - Role of alpha 2C-adrenoceptor translocation" 94 (94): 1367-1374, 2004

19 Sakurada S, "Rho activation in excitatory agonist-stimulated vascular smooth muscle" 281 (281): C571-C578, 2001

20 Ming XF, "Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells" 22 (22): 8467-8477, 2002

21 Hamilton NB, "Pericyte- mediated regulation of capillary diameter:a component of neurovascular coupling in health and disease" 2 : 5-, 2010

22 Herrick AL, "Pathogenesis of Raynaud's phenomenon" 44 (44): 587-596, 2005

23 Cooke JP, "Mechanisms of Raynaud's disease" 10 (10): 293-307, 2005

24 Cao YX, "Ligustilide induces vasodilatation via inhibiting voltage dependent calcium channel and receptor- mediated Ca2+influx and release" 45 (45): 171-176, 2006

25 Lee K, "Inhibitory effect of ucha-shinki-hwan on cold-mediated response in human dermal microvascular endothelial cells" 4 (4): 105-110, 2017

26 Kellogg DL, "In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges" 100 (100): 1709-1718, 2006

27 van Marken Lichtenbelt WD, "Implications of nonshivering thermogenesis for energy balance regulation in humans" 301 (301): R285-R296, 2011

28 Rintamäki H, "Human responses to cold" 49 (49): 29-31, 2007

29 Cho SG, "Herbal Prescription, DSGOST, Prevents Cold-Induced RhoA Activation and Endothelin-1 Production in Endothelial Cells" 2014 : 549307-, 2014

30 Zhou ZY, "Ferulic acid relaxed rat aortic, small mesenteric and coronary arteries by blocking voltage-gated calcium channel and calcium desensitization via dephosphorylation of ERK1/2 and MYPT1" 815 : 26-32, 2017

31 Kawamata H, "Enhanced expression of inducible nitric oxide synthase by Juzen-taiho-to in LPS-activated RAW264.7 cells, a murine macrophage cell line" 28 (28): 217-226, 2000

32 권구범, "Enhanced Neurite Outgrowth of Dorsal Root Ganglion Sensory Neurons after Sibjeondaebo-tang Treatment" 한의병리학회 24 (24): 681-687, 2010

33 Chen GP, "Endothelium-independent vasorelaxant effect of sodium ferulate on rat thoracic aorta" 84 (84): 81-88, 2009

34 Dehouck MP, "Endothelin-1 as a mediator of endothelial cell-pericyte interactions in bovine brain capillaries" 17 (17): 464-469, 1997

35 Kanai S, "Efficacy of Toki-Shigyakuka-Gosyuyu-Syokyo-To(Danggui-Sini-Jia-Wuzhuyu-Shengjiang-tang)on Peripheral Circulation in Autonomic Disorders" 25 (25): 69-78, 1997

36 Kumura Y, "Efficacy of Kampo Formula Tokishigyakukagoshuyushokyoto for Cold Syndrome Evaluated with a Novel Clinical Method using a Patient-based Questionnaire Database" 63 (63): 299-304, 2012

37 Tsai HY, "Effects of veratrine and paeoniflorin on the isolated rat aorta" 66 (66): 249-255, 1999

38 Kaneko T, "Effect of two different groups of Chinese medicines on nitric oxide production by mouse macrophage-like cells" 18 (18): 771-778, 2004

39 Tsukada R, "Effect of a Traditional Japanese Medicine Goshajinkigan, Tokishigyakukagoshuyushokyoto on the Warm and Cold Sense Threshold and Peripheral Blood Flow" 6 (6): 757-763, 2014

40 Lee K, "Danggui-Sayuk-Ga-Osuyu-Senggang- Tang ameliorates cold-induced vasoconstriction in vitro and in vivo" 14 (14): 4723-4728, 2016

41 Thompson-Torgerson CS, "Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin" 292 (292): H1700-5, 2007

42 Raffai G, "Cinnamaldehyde and cinnamaldehyde -containing micelles induce relaxation of isolated porcine coronary arteries:role of nitric oxide and calcium" 9 : 2557-2566, 2014

43 Parsons JT, "Cell adhesion:integrating cytoskeletal dynamics and cellular tension" 11 : 633-643, 2010