蟾蜍皮肤提取物QUB2419的降压作用及机制初探
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摘要
目的:考察QUB2419对高血压大鼠的降压作用及其作用机制。方法:采用自发性高血压大鼠(SHR)和肾性高血压大鼠(RHR),尾静脉注射给药,观察给药前后血压的变化;采用血管平滑肌细胞(VSMCs),考察QUB2419对血小板衍生生长因子-BB(PDGF-BB)诱导VSMCs增殖的抑制作用;采用人脐静脉内皮细胞(HUVECs),Western Blot方法考察QUB2419对细胞中内皮型一氧化氮合酶(eNOS)、腺苷酸活化蛋白激酶(AMPK)、蛋白激酶B (AKT)蛋白磷酸化的影响。结果:QUB2419给药后2 min即显著降低SHR和RHR的血压,且降压作用呈剂量依赖性。QUB2419能够显著抑制PDGF-BB诱导的VSMCs的增殖。QUB2419能够显著增加HUVECs中p-eNOS,p-AMPK和p-AKT的蛋白表达。结论:QUB2419可显著降低高血压大鼠的血压,并抑制血管平滑肌细胞的增殖,其降压机制可能与增加HUVECs中p-eNOS,p-AMPK和p-AKT的蛋白表达相关。
Objective: To investigate the antihypertensive effect of QUB2419 in hypertensive rats and the possible mechanism. Methods: Spontaneous hypertensive rats( SHR) and renal hypertensive rats( RHR) were used. QUB2419 was injected via caudal vein,and the changes in blood pressure after dosing were observed. In vascular smooth muscle cells( VSMCs),the inhibition effect of QUB2419 on proliferation induced by plateletderived growth factor-BB( PDGF-BB) was determined. The expression of phosphorylated endothelial nitric oxide synthase( p-NOS),phosphorylated AMP-activated protein kinase( p-AMPK),and phosphorylated protein kinase B( p-AKT) in human umbilical vein endothelial cells( HUVECs) were detected by Western Blot assay. Results:Two minutes after administration,QUB2419 reduced the blood pressure in SHR and RHR in a dose-dependent manner. QUB2419 inhibited PDGF-BB-induced proliferation in VSMCs,and increased the phosphorylation of e NOS,AMPK and AKT in HUVECs. Conclusion: QUB2419 reduces the blood pressure in hypertensive rats,and inhibits proliferation of HUVECs. The antihypertensive mechanism of QUB2419 may relate to increasing p-eNOS,p-AMPK and p-AKT in vascular cells.
Objective: To investigate the antihypertensive effect of QUB2419 in hypertensive rats and the possible mechanism. Methods: Spontaneous hypertensive rats( SHR) and renal hypertensive rats( RHR) were used. QUB2419 was injected via caudal vein,and the changes in blood pressure after dosing were observed. In vascular smooth muscle cells( VSMCs),the inhibition effect of QUB2419 on proliferation induced by plateletderived growth factor-BB( PDGF-BB) was determined. The expression of phosphorylated endothelial nitric oxide synthase( p-NOS),phosphorylated AMP-activated protein kinase( p-AMPK),and phosphorylated protein kinase B( p-AKT) in human umbilical vein endothelial cells( HUVECs) were detected by Western Blot assay. Results:Two minutes after administration,QUB2419 reduced the blood pressure in SHR and RHR in a dose-dependent manner. QUB2419 inhibited PDGF-BB-induced proliferation in VSMCs,and increased the phosphorylation of e NOS,AMPK and AKT in HUVECs. Conclusion: QUB2419 reduces the blood pressure in hypertensive rats,and inhibits proliferation of HUVECs. The antihypertensive mechanism of QUB2419 may relate to increasing p-eNOS,p-AMPK and p-AKT in vascular cells.
引文
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[2]姜林峰,莫汉明,张正龙,等.几种血管活性物质在高血压中的作用[J].甘肃医药,2016,35(10):748-750.
[3] OGBOZOR UD,OPENE M,RENTERIA LS,et al. Mechanism by which nuclear factor-kappa beta(NF-kB)regulates ovine fetal pulmonary vascular smooth muscle cell proliferation[J]. Mol Genet Metab Rep,2015,4(1):1-8.
[4]戴勇,彭武建,徐卓佳.“两肾一夹”肾性高血压大鼠模型改进[J].试验动物科学与管理,2006,23(2):60-62.
[5] FRY JL,SHIRAISHI Y,TURCOTTE R,et al. Vascular smooth muscle sirtuin-1 protects against aortic dissection during angiotensin ii-induced hypertension[J]. J Am Heart Assoc,2015,4(9):e002384.
[6] DONG LH,WEN JK,MIAO SB,et al. Baicalin inhibits PDGFBB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRbeta-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia[J].Cell Res,2010,20(11):1252-1262.
[7] ARICO A,GUADAGNIN E,FERRARESSO S,et al. Plateletderived growth factors and receptors in Canine Lymphoma[J]. J Comp Pathol,2014,151(4):322-328.
[8] RAJAPAKSE NW,HEAD GA,KAYE DM. Say NO to obesityrelated hypertension:role of the l-arginine-nitric oxide pathway[J]. Hypertension,2016,67(5):813-819.
[9] OEMAR BS,TSCHUDI MR,GODOY N,et al. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis[J]. Circulation,1998,97(25):2494-2498.
[10] LEVINE YC,LI GK,MICHEL T. Agonist-modulated regulation of AMP-activated protein kinase(AMPK)in endothelial cells[J]. J Biol Chem,2007,282(28):20351-20364.
[11] CHEN Z,PENG IC,SUN W,et al. AMP-activated protein kinasefunctionally phosphorylates endothelial nitric oxide synthase[J]. Circ Res,2009,104(4):496-505.
[12] ZHANG CX,PAN SN,MENG RS,et al. Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase endothelial nitric oxide synthase pathway in rats[J]. Clin Exp Pharmacol Physiol,2011,38(1):55-62.
[13]陈金成,张吟. AMPK与肝脏糖异生研究进展[J].中国现代应用药学,2017,34(7):1062-1067.
[14]赵艳梅,张建康,蔡兆斌,等. Akt抑制剂的临床研究进展[J].中国现代应用药学,2017,34(4):625-630.
[15] COHEN MV,PHILIPP S,KRIEG T,et al. Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways[J]. J Mol Cell Cardiol,2007,42(4):842-851.
[16] FU C,LI B,SUN Y,et al. Bradykinin inhibits oxidative stressinduced senescence of endothelial progenitor cells through the B2R/AKT/RB and B2R/EGFR/RB signal pathways[J]. Oncotarget,2015,6(28):24675-24689.