SPH3127通过ERK1/2/Cx43信号通路改善高血压大鼠血管重构  

SPH3127 Improves Vascular Remodeling in Hypertensive Rats Through ERK1/2-Cx43 Signaling Pathway

作　　者：李瑜[1] 朱雅泉 张昕[2] LI Yu;ZHU Yaquan;ZHANG Xin(Baotou Medical College,Inner Mongolia University of Science&Technology,Inner Mongolia 014040,China)

机构地区：[1]内蒙古科技大学包头医学院,呼和浩特014040 [2]包头医学院第一附属医院心功能科,014040

出　　处：《医学研究杂志》2024年第12期140-144,156,共6页Journal of Medical Research

基　　金：内蒙古自治区包头市鹿城英才计划项目(YFYRC-LCYC-2023001);内蒙古自治区高等学校“青年科技英才支持项目”(NJYT23075);内蒙古医学科学院公立医院科研联合基金科技项目(2023GLLH0193);包头医学院青年科技人才发展计划临床医学+流行病学多学科联合科研基金资助项目(BYJJ-DXK 2022035);包头医学院创新团队基金资助项目(byjj-yfytd-007);2022“草原英才”工程专项资金支持项目(CYYC230401)。

摘　　要：目的探讨肾素抑制剂SPH3127是否通过抑制ERK1/2/Cx43信号通路减轻血管重构达到降压和靶器官保护作用以及SPH3127对RAAS级联反应的阻断作用。方法选取75只健康雄性SD大鼠,将其分为假手术组、高血压模型组、SPH3127组、缬沙坦组和甘珀酸(Cx43抑制剂)组。测量收缩压(systolic blood pressure,SBP),收集大鼠血清及胸主动脉组织。酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)水平,苏木精-伊红染色观察大鼠胸主动脉形态学改变,测量管壁厚度(wall thickness,WT)、血管内径(internal diameter,ID)、壁厚/腔径比值(wall thickness/internal diameter,W/I)、管壁与管腔面积比值(wall-lumen ratio,WLR);Western blot法检测细胞外信号调节激酶1/2(extracellular regulated pretein kinase1/2,ERK1/2)、连接蛋白43(connexin 43,Cx43)、α-平滑肌肌动蛋白(α-smooth mouscle actin,α-SMA)、增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)、骨桥蛋白(osteopontin,OPN)蛋白表达情况。结果高血压模型组较假手术组大鼠SBP、AngⅡ水平升高,WT、ID、W/I、WLR均增大,PCNA、OPN、ERK1/2、Cx43表达水平升高,α-SMA表达水平降低(P<0.05);SPH3127组较高血压模型组SBP、AngⅡ表达水平均降低,WT、ID、W/I、WLR均减小,PCNA、OPN、ERK1/2、Cx43表达水平降低,α-SMA表达水平升高(P<0.05);SPH3127组AngⅡ表达水平低于缬沙坦组(P<0.05)。结论SPH3127能通过抑制AngⅡ的生成阻断RAAS级联反应而发挥降低血压、改善血管重构作用,其机制与其抑制ERK1/2/Cx43信号通路后PCNA、OPN表达水平降低,α-SMA表达水平增加有关。Objective To investigate whether the renin inhibitor SPH3127 attenuates vascular remodeling to achieve antihypertensive and target organ protective effects through inhibiting the ERK1/2/Cx43signaling pathway as well as the blocking effect of SPH3127 on the RAAS cascade response.Methods Seventy-five healthy male SD rats were divided into sham operation group,hypertension model group,SPH3127group,valsartan group and glyburide(Cx43 inhibitor)group.Systolic blood pressure(SBP)was measured,serum and thoracic aorta tissues were collected.AngiotensinⅡ(AngⅡ)level was detected by enzyme-linked immunosorbent assay(ELISA),morphological changes of thoracic aorta were observed by hematoxylin-eosin staining,wall thickness(WT),internal diameter(ID),wall thickness/internal diameter(W/I),wall-lumen ratio(WLR)were measured;Extracellular regulated pretein kinase1/2(ERK1/2),Connexin 43(Cx43),α-smooth mouscle actin(α-SMA),proliferating cell nuclear antigen(PCNA),osteopontin(OPN)protein expression was detected by Western blot.Results Compared with the sham operation group,SBP and AngⅡlevels were increased in the hypertension model group,WT,ID,W/I and WLR were enlarged,the expression levels of PCNA,OPN,ERK1/2 and Cx43 were increased,and the expression level ofα-SMA was decreased(P<0.05);compared with the hypertension model group,SBP and AngⅡlevels were decreased in the SPH3127group,and WT,ID,W/I,WLR were decreased,PCNA,OPN,ERK1/2,Cx43 expression levels were decreased,andα-SMA expression level was increased(P<0.05);the expression level of AngⅡin SPH3127group was lower than that in valsartan group(P<0.05).Conclusion SPH3127 can play a role in decreasing blood pressure and improving vascular remodeling by blocking the RAAS cascade reaction through the inhibition of AngⅡproduction,the mechanism of which is related to its inhibition of ERK1/2/Cx43signaling pathway after the reduction in the expression levels of PCNA,OPN,and the increase in the expression level ofα-SMA.

关 键 词：高血压 SPH3127 连接蛋白43 血管重构 细胞转导通路 

分 类 号：R544.1[医药卫生—心血管疾病]