绿原酸通过上调鞘氨醇-1-磷酸受体 1 抑制内质网应激来减轻心脏肥厚。

Chlorogenic acid attenuates cardiac hypertrophy via up-regulating Sphingosine-1-phosphate receptor1 to inhibit endoplasmic reticulum stress.

机构信息

General Station for Drug and Instrument Supervision and Control, Joint Logistic Support Force of Chinese People's Liberation Army, Beijing, China.

Central Laboratory, Hainan Hospital of Chinese People's Liberation Army General Hospital, Sanya, China.

出版信息

ESC Heart Fail. 2024 Jun;11(3):1580-1593. doi: 10.1002/ehf2.14707. Epub 2024 Feb 19.

DOI:10.1002/ehf2.14707

PMID:38369950

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11098655/

Abstract

AIMS

Cardiac hypertrophy, an adaptive response of the heart to stress overload, is closely associated with heart failure and sudden cardiac death. This study aimed to investigate the therapeutic effects of chlorogenic acid (CGA) on cardiac hypertrophy and elucidate the underlying mechanisms.

METHODS AND RESULTS

To simulate cardiac hypertrophy, myocardial cells were exposed to isoproterenol (ISO, 10 μM). A rat model of ISO-induced cardiac hypertrophy was also established. The expression levels of cardiac hypertrophy markers, endoplasmic reticulum stress (ERS) markers, and apoptosis markers were measured using quantitative reverse transcription PCR and western blotting. The apoptosis level, size of myocardial cells, and heart tissue pathological changes were determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling staining, immunofluorescence staining, haematoxylin and eosin staining, and Masson's staining. We found that CGA treatment decreased the size of ISO-treated H9c2 cells. Moreover, CGA inhibited ISO-induced up-regulation of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain), ERS markers (C/EBP homologous protein, glucose regulatory protein 78, and protein kinase R-like endoplasmic reticulum kinase), and apoptosis markers (bax and cleaved caspase-12/9/3) but increased the expression of anti-apoptosis marker bcl-2 in a dose-dependent way (0, 10, 50, and 100 μM). Knockdown of sphingosine-1-phosphate receptor 1 (S1pr1) reversed the protective effect of CGA on cardiac hypertrophy, ERS, and apoptosis in vitro (P < 0.05). CGA also restored ISO-induced inhibition on the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling in H9c2 cells, while S1pr1 knockdown abolished these CGA-induced effects (P < 0.05). CGA (90 mg/kg/day, for six consecutive days) protected rats against cardiac hypertrophy in vivo (P < 0.05).

CONCLUSIONS

CGA treatment attenuated ISO-induced ERS and cardiac hypertrophy by activating the AMPK/SIRT1 pathway via modulation of S1pr1.

摘要

目的

心肌肥厚是心脏对压力超负荷的适应性反应，与心力衰竭和心源性猝死密切相关。本研究旨在探讨绿原酸（CGA）对心肌肥厚的治疗作用，并阐明其潜在机制。

方法和结果

为模拟心肌肥厚，将心肌细胞暴露于异丙肾上腺素（ISO，10 μM）中。还建立了 ISO 诱导的心肌肥厚大鼠模型。使用定量逆转录 PCR 和 Western blot 测定心肌肥厚标志物、内质网应激（ERS）标志物和细胞凋亡标志物的表达水平。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色、免疫荧光染色、苏木精和伊红染色以及 Masson 染色测定细胞凋亡水平、心肌细胞大小和心脏组织病理变化。结果发现，CGA 处理可减小 ISO 处理的 H9c2 细胞的大小。此外，CGA 抑制 ISO 诱导的心肌肥厚标志物（心房利钠肽、脑利钠肽和β-肌球蛋白重链）、ERS 标志物（C/EBP 同源蛋白、葡萄糖调节蛋白 78 和蛋白激酶 R 样内质网激酶）和细胞凋亡标志物（bax 和 cleaved caspase-12/9/3）的上调，但以剂量依赖性方式增加抗凋亡标志物 bcl-2 的表达（0、10、50 和 100 μM）。S1 型鞘氨醇 1-磷酸受体 1（S1pr1）敲低逆转了 CGA 对体外心肌肥厚、ERS 和细胞凋亡的保护作用（P < 0.05）。CGA 还恢复了 ISO 诱导的 H9c2 细胞中 AMP 激活的蛋白激酶（AMPK）/沉默调节蛋白 1（SIRT1）信号的抑制作用，而 S1pr1 敲低则消除了这些 CGA 诱导的作用（P < 0.05）。CGA（90 mg/kg/天，连续 6 天）可防止体内 ISO 诱导的大鼠心肌肥厚（P < 0.05）。