我们的网站为什么显示成这样？

可能因为您的浏览器不支持样式，您可以更新您的浏览器到最新版本，以获取对此功能的支持，访问下面的网站，获取关于浏览器的信息：

|本期目录/Table of Contents|

PERK-ATF4-CHOP信号通路在褪黑素抵抗血管紧张素Ⅱ诱导乳鼠心肌细胞肥厚中的作用

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2018年第4期
页码:
383-387,399
栏目:
基础研究
出版日期:
2018-04-25

文章信息/Info

Title:
Role of PERK-ATF4-CHOP pathway in melatonin attenuates cardiomyocyte hypertrophy induced by angiotensin II
作者:
艾永飞; 刘 静; 尚福军; 苏菲菲; 曾广伟
(第四军医大学唐都医院心血管内科，陕西 西安 710038)
Author(s):
AI Yong-fei;  LIU Jing;  SHANG Fu-jun;  SU Fei-fei;  ZENG Guang-wei
(Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi, China)
关键词:
心肌肥厚; 褪黑素; PERK-ATF4-CHOP
Keywords:
cardiomyocyte hypertrophy;  melatonin;  PERK-ATF4-CHOP
分类号:
R364.3；R318.11
DOI:
-
文献标识码:
A
摘要:
目的 初步探讨内质网应激PERK-ATF4-CHOP通路在褪黑素抵抗血管紧张素Ⅱ（angiotensinⅡ,AngⅡ）诱导的心肌细胞肥厚中的作用。方法 将培养的心肌细胞随机分为对照组、AngⅡ处理组、褪黑素组。采用乳酸脱氢酶 (lactate dehydrogenase,LDH)法检测细胞活性，原位切口末端标记法（TUNEL）检测细胞凋亡率，Western blot检测蛋白激酶R样内质网激酶（protein kinase r-like endoplasmic reticulum kinase，PERK）、活性转录因子(Activating Transcription Factor，ATF)4、C/EBP同源蛋白(C/EBP homologous protein,CHOP)的表达水平，实时荧光定量聚合酶链反应(quantitative real-time polymerase chain reaction,qRT-PCR)检测心肌肥厚相关标识物心房钠尿肽(atrial natriuretic peptide,ANP)、脑钠尿肽(brain natriuretic peptide,BNP)和心肌β-肌球蛋白重链(β-myosin heavy chain,β-MHC) mRNA表达量的变化；免疫荧光检测心肌细胞横截面积。结果 与对照组相比，AngⅡ能够刺激心肌细胞上调ANP、BNP和β-MHC表达（P<0.05），刺激LDH释放（P<0.05）、增加细胞凋亡比率和心肌细胞横截面积（P<0.05）；与AngⅡ组相比，褪黑素可以浓度依赖性显著抑制AngⅡ诱导的ANP、BNP和β-MHC的上调和LDH的积累，抑制心肌细胞的横截面积增加，降低细胞凋亡，并抑制诱导的PERK-ATF4-CHOP通路的激活（P<0.05）；与对照组相比，AngⅡ显著增加PERK、ATF4和CHOP的表达水平（P<0.05），但给予褪黑素后，激活的PERK-ATF4-CHOP则被明显抑制（P<0.05）。结论 褪黑素可能通过抑制内质网应激PERK-ATF4-CHOP信号通路激活，改善AngⅡ诱导的乳鼠心肌细胞肥厚，为未来褪黑素的进一步临床研究拓展新思路。
Abstract:
AIM To explore the role of the PERK-ATF4-CHOP pathway in melatonin attenuated cardiomyocyte hypertrophy induced by angiotensin II (AngII). METHODS Cells were divided randomly into three groups: the blank control group, the AngII-stimulated group, the melatonin group. Lactate dehydrogenase (LDH) release was used to test cell viability. TUNEL staining was used to detect the apoptosis. Western blot method was used to detect the expression of PERK, ATF4 and CHOP. Real time-PCR was used to detect gene expression of ANP, BNP and β-MHC. Immunostaining was used to observe the cell morphology by α-actinin. RESULTS Compared with those in the control group, AngII pretreatment significantly augmented the expression of ANP, BNP and β-MHC, up-regulated LDH activity and apoptosis (P<0.05), and increased cell cross-sectional area of myocardial cells (P<0.05). Melatonin treatment resulted in reduction of expression of ANP, BNP and β-MHC (P<0.05), down-regulation of cardiomyocyte LDH activity and apoptosis (P<0.05), and the inhibition of cardiomyocyte hypertrophy (P<0.05). Moreover, Western blot analysis revealed that AngII exhibited a marked augmentation of the protein of ERK, ATF4 and CHOP (P<0.05), whereas melatonin suppressed the activation of ERK, ATF4 and CHOP stimulated by AngII (P<0.05). CONCLUSION SThe present study suggests that melatonin attenuates cardiomyocyte hypertrophy induced by AngII through the endoplasmic reticulum stress PERK-ATF4-CHOP signaling pathway. These results contribute to providing new therapeutic targets for future clinical treatment with melatonin.

参考文献/References

[1]Barrenetxe J,Delagrange P,Martínez JA.Physiological and metabolic functions of melatonin[J].J Physiol Biochem,2004,60(1):61-72.

[2]Cipolla-Neto J,Amaral FG,Afeche SC,et al.Melatonin, energy metabolism,and obesity:a review[J].J Pineal Res,2014,56(4):371-381.

[3]Favero G,Franceschetti L,Buffoli B,et al.Melatonin:Protection against age-related cardiac pathology[J].Ageing Res Rev,2017,35:336-349.

[4]Feldman AM,Weinberg EO,Ray PE,et al.Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding[J].Circ Res,1993,73(1):184-192.

[5]Ghosh G,De K,Maity S,et al.Melatonin protects against oxidative damage and restores expression of GLUT4 gene in the hyperthyroid rat heart[J].J Pineal Res,2007,42(1):71-82.

[6]ang Y,Sun Y,Yi W,et al.A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases[J].J Pineal Res,2014,57(4):357-366.

[7]Girouard H,Denault C,Chulak C,et al.Treatment by n-acetylcysteine and melatonin increases cardiac baroreflex and improves antioxidant reserve[J].Am J Hypertens,2004,17(10):947-954.

[8]Yeung HM,Hung MW,Fung ML. Melatonin ameliorates calcium homeostasis in myocardial and ischemia-reperfusion injury in chronically hypoxic rats[J].J Pineal Res,2008,45(4):373-382.

[9]Guzel E,Arlier S,Guzeloglu-Kayisli O,et al.Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology[J].Int J Mol Sci,2017,18(4).pii:E792.doi:10.3390/ijms18040792.

[10]Rani S,Sreenivasaiah PK,Cho C,et al.Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway[J].Mol Cells,2017,40(1):66-72.

[11]Chen Y,Gui D,Chen J,et al.Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats[J].Cell Physiol Biochem,2014,33(6):1975-1987.

[12]Yi S,Shi W,Wang H,et al.Endoplasmic Reticulum Stress PERK-ATF4-CHOP Pathway Is Associated with Hypothalamic Neuronal Injury in Different Durations of Stress in Rats[J].Front Neurosci,2017,11:152.

[13]Zou XJ,Yang L,Yao SL.Propofol depresses angiotensin II-induced cardiomyocyte hypertrophy in vitro[J].Exp Biol Med(Maywood),2008,233(2): 200-208.

[14]Chen Y,Yu S,Zhang N,et al.Atorvastatin prevents Angiotensin II induced myocardial hypertrophy in vitro via CCAAT/enhancer-binding protein beta[J].Biochem Biophys Res Commun,2017,486(2):423-430.

[15]Mahdi AA,Rizvi SH,Parveen A.Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases[J].Indian J Clin Biochem,2016,31(2):127-137.

[16]张嘉宾,张盼盼,王红阳,等.磷酸化蛋白激酶样内质网激酶、C/EBP同源蛋白在慢性间歇低氧大鼠肺组织中的表达变化及意义[J].中国现代医学杂志,2016,26(15):38-43.

[17]Liu X,Kwak D,Lu Z,et al.Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase(PERK)protects against pressure overload-induced heart failure and lung remodeling[J].Hypertension,2014,64(4):738-744.

[18]Liu Z,Shi Q,Song X,et al.Activating Transcription Factor 4(ATF4)-ATF3-C/EBP Homologous Protein(CHOP)Cascade Shows an Essential Role in the ER Stress-Induced Sensitization of Tetrachlorobenzoquinone-Challenged PC12 Cells to ROS-Mediated Apoptosis via Death Receptor 5 (DR5) Signaling[J].Chem Res Toxicol,2016,29(9):1510-1518.

备注/Memo

备注/Memo:
收稿日期：2017-06-27.基金项目：国家自然科学基金青年项目资助（81300077） 作者简介：艾永飞，主治医师，硕士 Email：434979751@qq.com
更新日期/Last Update: 1900-01-01