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慢性心理应激通过糖皮质激素促进主动脉中膜钙化

李艳青¹, 黄盼娜², 张淏喆², 韩蕗羽², 苗若湘², 冯莞芸², 潘华³, 冯林⁴, 吴新华⁴, 何娟⁴, 滕旭^2,*, 王晓宁⁴

¹河北省中医院妇科，石家庄 050011；²河北医科大学生理学教研室，石家庄 050017；³河北省中医院医务处，石家庄 050011；⁴河北医科大学第二医院儿科，石家庄 050000

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D3 (vitamin D3, VitD3)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VitD3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VitD3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。

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 exacerbates aortic medial calcification via glucocorticoids

LI Yan-Qing¹, HUANG Pan-Na², ZHANG Hao-Zhe², HAN Lu-Yu², MIAO Ruo-Xiang², FENG Wan-Yun², PAN Hua³, FENG Lin⁴, WU Xin-Hua⁴, HE Juan⁴, TENG Xu^2,*, WANG Xiao-Ning⁴

¹Department of Gynaecology, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050011, China；²Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China；³Medical Services Section, Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050011, China；⁴Department of Pediatrics, the Second Hospital of Hebei Medical University, Shijiazhuang 050000, China

Abstract

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 D3 (VitD3) 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 VitD3, 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 VitD3, 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.

Key words: chronic psychological stress; vascular calcification; glucocorticoids; endoplasmic reticulum stress

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通讯作者：滕旭　　E-mail: tengxu78@hebmu.edu.cn

引用本文：

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. 慢性心理应激通过糖皮质激素促进主动脉中膜钙化[J]. 生理学报 2022; 74 (6): 927-938.

LI Yan-Qing, HUANG Pan-Na, ZHANG Hao-Zhe, HAN Lu-Yu, MIAO Ruo-Xiang, FENG Wan-Yun, PAN Hua, FENG Lin, WU Xin-Hua, HE Juan, TENG Xu, WANG Xiao-Ning. Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids. Acta Physiol Sin 2022; 74 (6): 927-938 (in Chinese with English abstract).