黄连解毒汤对自发性高血压大鼠心脏内质网应激的影响

doi:10.5246/jcps.2024.07.045

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (7): 609-619.DOI: 10.5246/jcps.2024.07.045

黄连解毒汤对自发性高血压大鼠心脏内质网应激的影响

张晓明¹^,^#, 朱世慧¹^,^#, 高艺文¹, 李建橡², 张楠¹^,^*(), 岳桂华³^,^*()

^1. 滨州医学院烟台附属医院, 山东烟台 264100
^2. 广西中医药大学附属瑞康医院, 广西南宁 530000
^3. 广西中医药大学, 广西南宁 530000

收稿日期:2023-11-21 修回日期:2023-12-23 接受日期:2024-01-08 出版日期:2024-07-30 发布日期:2024-07-30
通讯作者: 张楠, 岳桂华

Effect of Huanglian Jiedu Decoction on cardiac endoplasmic reticulum stress in spontaneously hypertensive rats

Xiaoming Zhang¹^,^#, Shihui Zhu¹^,^#, Yiwen Gao¹, Jianxiang Li², Nan Zhang¹^,^*(), Guihua Yue³^,^*()

¹ Yantai Affiliated Hospital of Binzhou Medical College, Yantai 264100, Shandong, China
² Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning 530000, Guangxi, China
³ Guangxi University of Traditional Chinese Medicine, Nanning 530000, Guangxi, China

Received:2023-11-21 Revised:2023-12-23 Accepted:2024-01-08 Online:2024-07-30 Published:2024-07-30
Contact: Nan Zhang, Guihua Yue
About author:
^# Xiaoming Zhang and Shihui Zhu contributed equally to this work.
Supported by:
The National Natural Science Foundation of China (Grant No. 81860831) and the Shandong Provincial Key Project of Traditional Chinese Medicine Science and Technology (Grant Nos. M-2023170, M-2022233).

摘要/Abstract

摘要：

黄连解毒汤为清热解毒的代表方, 主要用于治疗三焦火毒热盛证。肝火亢盛是高血压常见的证型, 风火炽盛、风毒内生是高血压的重要病机。本研究目的是观察黄连解毒汤(Huanglian Jiedu decoction, HLJDD)对自发性高血压大鼠(Spontaneous hypertension rat, SHR)内质网的影响, 进一步探讨内质网应激(ERS)与心肌重塑、损伤的相互关系。将50只SHR大鼠随机分为模型组、HLJDD低剂量、中剂量、高剂量组以及卡托普利组5个组别, 另设Wistar-Kyoto(WKY)大鼠为空白对照组, 每组各10只。除模型组和空白对照组灌胃给予等体积的生理盐水外, 其余各组分别灌胃给予相应剂量药物, 每天1次, 共6周。实验末, 进行心脏重量指数(HWI)和左心室重量指数(LVWI)值检测, HE染色检测心脏组织病理变化, Western blotting和qPCR检测内质网应激相关蛋白和mRNA表达水平变化, TUNEL染色检测心肌细胞凋亡。结果发现黄连解毒汤各组随着黄连解毒汤浓度的增加, 小鼠心脏的HWI和LVWI升高(P < 0.05), 心肌结构损伤明显改善、胶原纤维明显减少, 黄连解毒汤中、高剂量组显著降低心肌肌醇依赖酶1α(IRE1α)、 X盒结合蛋白1(XBP1)、糖调节蛋白78(GRP78)、CCAAT增强子结合蛋白同源蛋白(CHOP)的mRNA和蛋白表达(P < 0.05), 作用同卡托普利组。本研究HLJDD有效改善SHR心肌组织损伤, 其分子机制可能是下调IRE1α、XBP1、GRP78、CHOP表达, 抑制过度的内质网应激, 减少心肌细胞的凋亡, 从而发挥对心脏的保护作用。

关键词: 黄连解毒汤, 自发性高血压, 内质网应激, 心肌重塑, IRE1α, XBP1, GRP78, CHOP

Abstract:

Huanglian Jiedu Decoction (HLJDD) is a quintessential prescription renowned for its heat-clearing and detoxifying properties. It is primarily prescribed to counteract the syndrome characterized by the excessive heat of the Sanjiao fire. Notably, the hyperactivity of liver fire is frequently linked with hypertension, where wind fire and wind toxicity emerge as pivotal pathogenic factors. This study aimed to investigate the impact of HLJDD on the endoplasmic reticulum in spontaneously hypertensive rats (SHR), further delving into the interplay between endoplasmic reticulum stress (ERS) and myocardial remodeling and damage. Fifty SHR rats were stratified randomly into five cohorts: model, low-dose HLJDD, medium-dose HLJDD, high-dose HLJDD, and captopril groups. For comparison, a set of Wistar-Kyoto (WKY ) rats served as the baseline control group, with each group comprising 10 rats. While the model and control groups received equivalent volumes of normal saline via gavage, the other groups were administered the respective drug dosages through the same route daily for a span of 6 weeks. Upon the experiment’s conclusion, metrics such as the heart mass index (HWI) and left ventricular mass index (LVWI) were assessed. Cardiac tissue anomalies were identified using H&E staining, while ERS-related protein and mRNA expression levels were ascertained via Western blotting analysis and qPCR. Moreover, TUNEL staining was employed to detect cardiomyocyte apoptosis. The findings indicated that increasing HLJDD concentrations corresponded with escalated HWI and LVWI in rat hearts (P < 0.05). There was a marked enhancement in myocardial structural integrity, accompanied by a notable reduction in collagen fibers. The mRNA and protein expressions of myocardial inositol-dependent enzyme 1α (IRE1α), X-box binding protein 1 (XBP1), glycoregulatory protein 78 (GRP78), and CCAAT enhancer binding protein homologous protein (CHOP) in the medium and high-dose groups saw significant declines (P < 0.05). These effects mirrored those observed in the captopril group. The study underscored HLJDD’s efficacy in mitigating myocardial tissue damage in SHR. This therapeutic effect was potentially attributed to the downregulation of IRE1α, XBP1, GRP78, and CHOP, curbing excessive ERS, diminishing cardiomyocyte apoptosis, and thereby conferring cardioprotection.

Key words: Huanglian Jiedu Decoction, Spontaneous hypertension, Endoplasmic reticulum stress, Myocardial remodeling, IRE1α, XBP1, GRP78, CHOP

Supporting:

张晓明, 朱世慧, 高艺文, 李建橡, 张楠, 岳桂华. 黄连解毒汤对自发性高血压大鼠心脏内质网应激的影响[J]. 中国药学(英文版), 2024, 33(7): 609-619.

Xiaoming Zhang, Shihui Zhu, Yiwen Gao, Jianxiang Li, Nan Zhang, Guihua Yue. Effect of Huanglian Jiedu Decoction on cardiac endoplasmic reticulum stress in spontaneously hypertensive rats[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(7): 609-619.

图/表 10

Table 1. qPCR primer information.

Table 2. Test results of myocardial hypertrophy-related indexes in each group.

Figure 1. Pathological changes of cardiac tissue of rats in each group (H&E, ×200).

Table 3. Expression of IRE1α, XBP1, GRP78, and CHOP mRNA.

Figure 2. Expression of IRE1α, XBP1, GRP78, and CHOP mRNA. Note: *P < 0.05 compared with the blank control group; #P < 0.05 compared with the model group.

Figure 3. Expression of IRE1α, XBP1, GRP78, and CHOP in the ventricular muscle of rats in each group.

Figure 4. Expression of IRE1α, XBP1, GRP78, and CHOP in the ventricular muscle of rats in each group. Note: *P < 0.05 compared with the blank control group; #P < 0.05 compared with the model group.

Table 4. Expression of IRE1α, XBP1, GRP78, and CHOP in the ventricular muscle of rats in each group.

Figure 5. TUNEL staining of ventricular Muscle cell of rats in each group (×100).

Figure 6. The apoptosis rate of cardiac cells in each group. Note: *P < 0.05 compared with the blank control group; #P < 0.05 compared with the model group.

参考文献 18

[1]	Chun, Y.H.; Dang, H.W.; Yan, Y.J. Effects of endoplasmic reticulum stress in cardiovascular diseases. J. Clin. Cardiol. 2015, 31, 1018–1022.
[2]	Qian, Z.Q.; Yang, D.L. Advances in the role of endoplasmic reticulum stress in ventricular remodeling. Chin. J. New Med. Clin. Med. 2016, 9, 615–620.
[3]	Lin, K.; Zhao, L.Y.; Huang, J.Y. Expression of GRP78 and CHOP in endoplasmic reticulum stress in hypertensive rats and their relationship with myocardial apoptosis. J. Cardiology. 2010, 22, 828–832.
[4]	Ding, S.W.; Li, X.; Li, Y.L. Construction and application of heat toxicity theory in heart system diseases. J. Shandong Univ. Chin. Med. 2004, 28, 413.
[5]	Nan, Z. Effect of Huanglian Jiedu Decoction on vascular endothelium factor and expression of RhoA protein factor in young spontaneously hypertensive rats. J. Chin. Pharm. Sci. 2019, 28, 114–120.
[6]	Gao, Y.W.; Zhang, N.; Zhang, Z.; Zhang, J.; Yue, G.H. Effect of Huanglian Jiedu Decoction on the expression of endothelial nitric oxide synthase in aorta of young spontaneously hypertensive rats. Lishizhen Med. Mater. Med. Res. 2012, 23, 2684–2685.
[7]	Gao, Y.W.; Zhang, N.; Lv, C.M.; Yang, X.M.; Yue, G.H. Effects of Huanglianjiedu Decoction on vascular endothelial NO pathway in young spontaneously hypertensive rats. Chin. J. Clin. Pharm. Ther. 2019, 24, 248–253.
[8]	Yue, G.H.; Qin, X.H. Material basis of "toxicity" in hypertension. Chin. J. Basic Med. Tradit. Chin. Med. 2009, 15, 133–134.
[9]	Liu, L.; Wang, S.Y.; Li, Y.L. Exploration of the theory of the pathogenesis of heart liver fire and heat toxicity in primary hypertension based on systematic evaluation. J. Shandong Univ. Tradit. Chin. Med. 2010, 34, 397–400.
[10]	He, L.M.; Wang, H.; Zhao, H.Y. The effect of baicalin on blood pressure and inhibition of left ventricular remodeling in renal hypertensive rats. Chin. J. Atheroscler. 2017, 25, 693–700.
[11]	Sun, X.W.; Chen, L.G.; Wang, H.Q.; Qu, Y.; Yan, L.; Tang, H.L. Study on the mechanism of endoplasmic reticulum stress cell apoptosis in vascular endothelial injury of hypertension with blood stasis syndrome. Chin. J. Tradit. Chin. Med. 2015, 30, 3368–3371.
[12]	Yue, G.H.; Gai, X.; Zhang, A.Z. Preliminary exploration of self-organization theory and hypertension. Shandong J. Tradit. Chin. Med. 1999, 3, 5–6.
[13]	Liu, J.; Zhao, L.Y.; Li, X. Amlodipine reduces myocardial endoplasmic reticulum stress in abdominal aorta constriction hypertensive rats. Basic Med. Clin. Sci. 2018, 38, 80–86.
[14]	Yang, X.Y.; Lu, F.E.; Huang, L.; Chen, G.; Wang, Z.Q. Effect of Huanglian Jiedu Decoction and Huanglian Decoction on oxidative stress and endoplasmic reticulum stress in insulin resistance rats. Chin. J. Hosp. Pharm. 2008, 28, 1433–1437.
[15]	Zhao, Y. Effect of berberine on endoplasmic reticulum stress in insulin resistance rats. Wuhan Huazhong Univ. Sci. Technol.
[16]	Yang, L. Effect of baicalin on endoplasmic reticulum stress-induced cardiomyocyte injury induced by itimycin. Xi’an The Fourth Military Med. Univ.
[17]	Xiao, P.G.; Xiao, W.; Xu, L.J.; He, C.N.; Peng, Y.; Jiang, B.P.; Hu, K.P. Coptis coptis and Chinese herbs containing berberine alkaloids. Chin. J. Modern Chin. Med. 2016, 18, 1381–1385.
[18]	Zhang, Z.Y.; Liu, X.H. Endoplasmic reticulum stress in vascular endothelial cells. Prog. Physiol. Sci. 2010, 41, 295–298.

黄连解毒汤对自发性高血压大鼠心脏内质网应激的影响

Effect of Huanglian Jiedu Decoction on cardiac endoplasmic reticulum stress in spontaneously hypertensive rats

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