摘要
长期的慢性心理应激可导致或促进高血压、动脉粥样硬化等心血管病变,本研究旨在探讨长期的慢性心理应激对主动脉中膜钙化(aortic medial calcification,AMC)的影响和机制。用尼古丁灌胃联合维生素D_(3)(vitamin D_(3),VitD_(3))肌注制备大鼠动脉钙化模型,用潮湿环境诱导建立大鼠慢性心理应激模型,用茜素红染色、主动脉钙含量和碱性磷酸酶活性测定评价大鼠主动脉钙化程度,用Western blot检测相关蛋白表达水平,包括血管平滑肌细胞收缩表型标志分子SM22α、成骨细胞样表型标志分子RUNX2以及内质网应激(endoplasmic reticulum stress,ERS)标志分子GRP78和CHOP。研究结果显示,单独慢性心理应激即可引起大鼠AMC,也可进一步加重尼古丁联合VitD_(3)诱导的AMC,促进血管平滑肌细胞成骨细胞样表型转化和ERS激活,显著提高血浆皮质醇水平。11β-羟化酶抑制剂美替拉酮有效降低慢性心理应激诱导的血浆皮质醇水平,改善慢性心理应激模型大鼠AMC和主动脉ERS。反之,糖皮质激素受体激动剂地塞米松可引起AMC,也可促进尼古丁联合VitD_(3)诱导的AMC,并且进一步激活主动脉ERS。地塞米松的上述作用可被ERS抑制剂4-苯丁酸抑制。上述研究结果提示慢性心理应激可通过促进糖皮质激素合成导致AMC的发生、发展,这可能为AMC的防治提供新的策略和靶点。
Chronic psychological stress can promote vascular diseases,such as hypertension and atherosclerosis.This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification(AMC).Rat arterial calcification model was established by nicotine gavage in combination with vitamin D_(3)(VitD_(3))intramuscular injection,and rat model of chronic psychological stress was induced by humid environment.Aortic calcification in rats was evaluated by using Alizarin red staining,aortic calcium content detection,and alkaline phosphatase(ALP)activity assay.The expression levels of the related proteins,including vascular smooth muscle cells(VSMCs)contractile phenotype marker SM22α,osteoblast-like phenotype marker RUNX2,and endoplasmic reticulum stress(ERS)markers(GRP78 and CHOP),were determined by Western blot.The results showed that chronic psychological stress alone induced AMC in rats,further aggravated AMC induced by nicotine in combination with VitD_(3),promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation,and significantly increased the plasma cortisol levels.The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats.Conversely,the glucocorticoid receptor agonist dexamethasone induced AMC,promoted AMC induced by nicotine combined with VitD_(3),and further activated aortic ERS.The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate.These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis,which may provide new strategies and targets for the prevention and control of AMC.
作者
李艳青
黄盼娜
张淏喆
韩蕗羽
苗若湘
冯莞芸
潘华
冯林
吴新华
何娟
滕旭
王晓宁
LI Yan-Qing;HUANG Pan-Na;ZHANG Hao-Zhe;HAN Lu-Yu;MIAO Ruo-Xiang;FENG Wan-Yun;PANHua;FENG Lin;WU Xin-Hua;HE Juan;TENG Xu;WANG Xiao-Ning(Department of Gynaecology,Hebei Provincial Hospital of Traditional Chinese Medicine,Shijiazhuang 050011,China;Department of Physiology,Hebei Medical University,Shijiazhuang 050017,China;Department of Pediatrics,the Second Hospital of Hebei Medical University,Shijiazhuang 050000,China;Medical Services Section,Hebei Provincial Hospital of Traditional Chinese Medicine,Shijiazhuang 050011,China)
出处
《生理学报》
CAS
CSCD
北大核心
2022年第6期927-938,共12页
Acta Physiologica Sinica
基金
supported by the National Natural Science Foundation of China(No.81770499 and 31871154)
the Natural Science Foundation of Hebei Province,China(No.H2020206350)
关键词
慢性心理应激
血管钙化
糖皮质激素
内质网应激
chronic psychological stress
vascular calcification
glucocorticoids
endoplasmic reticulum stress
作者简介
通讯作者:滕旭,生理学博士,河北医科大学生理学教研室教授、博士生导师,健康研究院心血管医学中心PI,兼任石家庄市第十四届政协委员、中国生理学会和河北省生理科学会理事、《比较医学杂志》编委、民盟河北省委社会委员会委员,入选河北省“三三三人才”、河北省高等学校科学研究优秀青年。主要从事血管中膜钙化发生的分子机制及其调控研究,以及血压稳态的维持和自主神经功能的研究,研究成果获中华医学会科学技术三等奖、河北省科技进步二等奖、自然科学三等奖各1项,已发表SCI论文50余篇,总引用次数1100余次,H-index为21,代表性论文发表于Cardiovasc Res、Acta Pharmacol Sin、Biomed Pharmacother、Front Pharm等中科院分区Top期刊,主持国家自然科学基金2项、河北省自然科学基金等省部级课题4项。Tel:+86-311-86266464,E-mail:tengxu78@hebmu.edu.cn;Corresponding author:WANG Xiao-Ning:Tel:+86-311-66002938,E-mail:wxnkylw@163.com;李艳青,黄盼娜,These authors contributed equally to this work
