ELA/APJ通过上调miR-133a抑制心肌细胞在缺血缺氧条件下凋亡的机制研究

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Abstract Objective To investigate the effect of ELABELA (ELA), which is a ligand of angiotensin receptor AT1 associated endogenous protein (APJ), on cardiomyocytes apoptosis under ischemia-hypoxia condition and to explore the regulatory mechanism of miR-133a. Methods The cardiomyocytes were cultured for 24 h under ischemia-hypoxia conditions (without serum, 1% O2) and divided into control group, ELA treatment group, ELA+siAPJ group, ELA+siAPJ NC group, ELA+miR-133a inhibitor group and ELA+miR-133a inhibitor NC group. The expression of myocardial α-actin (α-SA) and cardiac troponin T (cTnT) were observed by immunofluorescence. Flow cytometry was used to detect apoptosis. Western blot and qRT-PCR were used to detect the expression of APJ and miR-133a. Results ①Compared with the control group, the rate of early and late apoptosis in ELA treatment group was significantly decreased (P ＜ 0.01); ②compared with corresponding NC group, the early and late apoptosis rate of ELA+siAPJ group and ELA+miR-133a inhibitor group were significantly increased (P ＜ 0.01); ③the expression of APJ and miR-133a in ELA treatment group was significantly higher than that in control group after 24 h culture (P ＜ 0.01); ④after blocking the expression of APJ and miR-133a by siRNA, compared with that in the corresponding NC group, the protein and mRNA expression level of APJ and mRNA expression level of miR-133a were significantly decreased in ELA+siAPJ group (P ＜ 0.01). The protein and mRNA expression level of APJ did not change significantly in ELA+miR-133a inhibitor group (P ＞ 0.05), but the mRNA expression level of miR-133a was significantly decreased (P ＜ 0.01). Conclusion ELA could inhibit the apoptosis of cardiomyocytes in ischemic and hypoxic environment. This effect might be related to up-regulation of miR-133a after activation of APJ.

Key words： ELABELA Angiotensin receptor AT1 related receptor protein Ischemia-hypoxia Cardiomyocyte Cell apoptosis

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	CHEN Xuxiang1 HOU Jingying1 LONG Huibao1 WU Hao1 WU Quanhua1 YANG Huan1 FU Jiaying1 WANG Tong2

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CHEN Xuxiang1 HOU Jingying1 LONG Huibao1 WU Hao1 WU Quanhua1 YANG Huan1 FU Jiaying1 WANG Tong2. Research on the mechanism of ELA/APJ inhibiting the apoptosis of cardiomyocyte under the condition of ischemia and hypoxia by up-regulating miR-133a[J]. 中国医药导报, 2019, 16(15): 12-17.

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http://www.yiyaodaobao.com.cn/EN/ OR http://www.yiyaodaobao.com.cn/EN/Y2019/V16/I15/12

[1] Deyell MW，Krahn AD，Goldberger JJ. Sudden cardiac death risk stratification [J]. Circ Res，2015，116（12）：1907-1918.
[2] Mozaffarian D，Benjamin EJ，Go AS，et al. Heart disease and stroke statistics-2015 update：a report from the American Heart Association [J]. Circulation，2015，131（4）：e29-e322.
[3] Yang P，Read C，Kuc RE，et al. Elabela/Toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension [J]. Circulation，2017，135（12）：1160-1173.
[4] Kuba K，Sato T，Imai Y，et al. Apelin and Elabela/Toddler：double ligands for APJ/Apelin receptor in heart development physiology and pathology [J]. Peptides，2019， 111：62-70.
[5] Deng C，Chen H，Yang N，et al. Apela regulates fluid homeostasis by binding to the APJ receptor to activate Gi signaling [J]. J Biol Chem，2015，290（30）：18261-18268.
[6] Sato T，Sato C，Kadowaki A，et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin Ⅱ-induced cardiac damage [J]. Cardiovasc Res，2017，113（7）：760-769.
[7] Cao J，Li H，Chen L. Targeting drugs to APJ receptor：the prospect of treatment of hypertension and other cardiovascular diseases [J]. Curr Drug Targets，2015，16（2）：148-155.
[8] Murza A，Sainsily X，Coquerel D，et al. Discovery and structure-activity relationship of a bioactive fragment of ELABELA that modulates vascular and cardiac functions [J]. Med Chem，2016，59（7）：2962-2972.
[9] Hodgkinson CP，Kang MH，Dal-Pra S，et al. MicroRNAs and cardiac regeneration [J]. Circ Res，2015，116（10）：1700-1711.
[10] Li N，Zhou H，Tang Q. miR-133：A Suppressor of Cardiac Remodeling？[J]. Front Pharmacol，2018，9：903.
[11] Liu Y，Liang Y，Zhang JF，et al. MicroRNA-133 mediates cardiac diseases：Mechanisms and clinical implications [J]. Exp Cell Res，2017，354（2）：65-70.
[12] Chen LJ，Xu R，Yu HM，et al. The ACE2/Apelin signaling microRNAs and hypertension [J]. Int J Hypertens，2015， 2015：896861.
[13] Sahoo S，Losordo DW. Exosomes and cardiac repair after myocardial infarction [J]. Circ Res，2014，114（2）：333-344.
[14] Ong S，Ligons DL，Barin JG，et al. Natural Killer Cells Limit Cardiac Inflammation and Fibrosis by Halting Eosinophil Infiltration [J]. Am J Pathol，2015，185（3）：847-861.
[15] Pauli A，Norris ML，Valen E，et al. Toddler：an embryonic signal that promotes cell movement via Apelin receptors [J]. Science，2014，343（6172）：1248636.
[16] Wang Z，Yu D，Wang M，et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems [J]. Sci Rep，2015，5：8170.
[17] Perjés ?魣，Kilpi?觟 T，Ulvila J，et al. Characterization of apela，a novel endogenous ligand of apelin receptor in the adult heart [J]. Basic Res Cardiol，2016，111（1）：2.
[18] Helker CS，Schuermann A，Pollmann C，et al. The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis [J]. ELife，2015，4：06726.
[19] Xie F，Lv D，Chen L，et al. ELABELA：a novel hormone in cardiac development acting as a new endogenous ligand for the APJ receptor [J]. Acta Biochim Biophys Sin（Shanghai），2014，46（7）：620-622.
[20] Wystub K，Besser J，Bachmann A，et al. miR-1/133a clusters cooperatively specify the cardiomyogenic lineage by adjustment of myocardin levels during embryonic heart development [J]. PLoS Genet，2013，9（9）：e1003793.
[21] Chen S，Puthanveetil P，Feng B，et al. Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes [J]. Cell Mol Med，2014，18（3）：415-421.
[22] Lzarra A，Moscoso I，Levent E，et al. miR-133a enhances the protective capacity of cardiac progenitors cells after myocardial [J]. Stem Cell Reports，2014，3（6）：1029-1042.
[23] Jayawardena TM，Finch EA，Zhang L，et al. MicroRNA induced cardiac reprogramming in vivo：evidence for mature cardiac myocytes and improved cardiac function [J]. Circ Res，2015，116（3）：418-424.