Preeclampsia (PE) is a major cause of the pregnancy morbidity and mortality over the world. Disorganized placentation caused by trophoblast cell abnormity is one of main risk factors to induce PE. MiR-133a-3p has been shown to contain regulatory effects on oxidative stress in the cardiomyocytes. But the effects of miR-133a-3p on oxidative stress-induced apoptosis in the trophoblast cells remain unknown. In this study, trophoblast HTR-8/SVneo cells were transfected with miR-133a-3p mimics and inhibitor. H2O2 (250 microM) treatment of cells was adopted to induce oxidative stress. A series of typical molecular and cellular experiments was subsequently performed in order to investigate this issue. It was found that miR-133a-3p overexpression attenuated the oxidative stress induced by H2O2 through reduced ROS and MDA levels and enhanced antioxidase activities in the trophoblast cells. Overexpressed miR-133a-3p was shown to relieve the oxidative stress-induced apoptosis of HTR-8/SVneo cells. At molecular levels, a direct binding effect of miR-133a-3p on BACH1 was verified. Moreover, miR-133a-3p overexpression also enhanced BACH1 downstream Nrf2/HO-1 signaling to activate antioxidant genes. It is collectively demonstrated that miR-133a-3p can relieve the oxidative stress-induced apoptosis in the trophoblast cells through the BACH1/Nrf2/HO-1 signaling pathway via targeting BACH1 directly. This regulatory mechanism of miR-133a-3p in the trophoblast cells under oxidative stress may give a new perspective for oxidative stress-induced trophoblast cell abnormality and be useful to study more pathological mechanisms of PE.

Department of Obstetrics The 4th Hospital of Hebei Medical University Shijiazhuang Hebei People's Republic of China

Zobrazit více v PubMed

ACKERMAN WE, BUHIMSCHI IA, EIDEM HR, RINKER DC, ROKAS A, ROOD K, ZHAO G, SUMMERFIELD TL, LANDON MB, BUHIMSCHI CS. Comprehensive RNA profiling of villous trophoblast and decidua basalis in pregnancies complicated by preterm birth following intra-amniotic infection. Placenta. 2016;44:23–33. doi: 10.1016/j.placenta.2016.05.010. PubMed DOI PMC

AL-JAMEIL N, AZIZ KHAN F, FAREED KHAN M, TABASSUM H. A brief overview of preeclampsia. J Clin Med Res. 2014;6:1–7. doi: 10.4021/jocmr1682w. PubMed DOI PMC

GIUDICE A, ARRA C, TURCO MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol. 2010;647:37–74. doi: 10.1007/978-1-60761-738-9_3. PubMed DOI

GONG Y, REN J, LIU K, TANG LM. Tumor suppressor role of miR-133a in gastric cancer by repressing IGF1R. World J Gastroenterol. 2015;21:2949–2958. doi: 10.3748/wjg.v21.i10.2949. PubMed DOI PMC

GROTEGUT CA. Prevention of preeclampsia. J Clin Invest. 2016;126:4396–4398. doi: 10.1172/JCI91300. PubMed DOI PMC

HROMADNIKOVA I, KOTLABOVA K, IVANKOVA K, VEDMETSKAYA Y, KROFTA L. Profiling of cardiovascular and cerebrovascular disease associated microRNA expression in umbilical cord blood in gestational hypertension, preeclampsia and fetal growth restriction. Int J Cardiol. 2017;249:402–409. doi: 10.1016/j.ijcard.2017.07.045. PubMed DOI

JI F, ZHANG H, WANG Y, LI M, XU W, KANG Y, WANG Z, WANG Z, CHENG P, TONG D, LI C, TANG H. MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting Bcl-xL and Mcl-1. Bone. 2013;56:220–226. doi: 10.1016/j.bone.2013.05.020. PubMed DOI

JYRKKÄNEN HK, KUOSMANEN S, HEINÄNIEMI M, LAITINEN H, KANSANEN E, MELLA-AHO E, LEINONEN H, YLÄ-HERTTUALA S, LEVONEN AL. Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2. Biochem J. 2011;440:167–174. doi: 10.1042/BJ20110526. PubMed DOI

KUMAR D, LOU H, SINGAL PK. Oxidative stress and apoptosis in heart dysfunction. Herz. 2002;27:662–668. doi: 10.1007/s00059-002-2430-3. PubMed DOI

LI AY, YANG Q, YANG K. miR-133a mediates the hypoxia-induced apoptosis by inhibiting TAGLN2 expression in cardiac myocytes. Mol Cell Biochem. 2015a;400:173–181. doi: 10.1007/s11010-014-2273-2. PubMed DOI

LI P, NIJHAWAN D, BUDIHARDJO I, SRINIVASULA SM, AHMAD M, ALNEMRI ES, WANG X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479–489. doi: 10.1016/S0092-8674(00)80434-1. PubMed DOI

LI S, XIAO FY, SHAN PR, SU L, CHEN DL, DING JY, WANG ZQ. Overexpression of microRNA-133a inhibits ischemia-reperfusion-induced cardiomyocyte apoptosis by targeting DAPK2. J Hum Genet. 2015b;60 doi: 10.1038/jhg.2015.96. PubMed DOI

LV Y, LU C, JI X, MIAO Z, LONG W, DING H, LV M. Roles of microRNAs in preeclampsia. J Cell Physiol. 2019;234:1052–1061. doi: 10.1002/jcp.27291. PubMed DOI

MAJALI-MARTINEZ A, BARTH S, LANG U, DESOYE G, CERVAR-ZIVKOVIC M. Temporal changes of the endothelin system in human cytotrophoblasts during the first trimester of pregnancy. Physiol Res. 2018;67(Suppl 1):S247–S255. doi: 10.33549/physiolres.933828. PubMed DOI

MOL BWJ, ROBERTS CT, THANGARATINAM S, MAGEE LA, De GROOT CJM, HOFMEYR GJ. Pre-eclampsia. Lancet. 2016;387:999–1011. doi: 10.1016/S0140-6736(15)00070-7. PubMed DOI

PU M, CHEN J, TAO Z, MIAO L, QI X, WANG Y, REN J. Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cell Mol Life Sci. 2019;76:441–451. doi: 10.1007/s00018-018-2940-7. PubMed DOI PMC

REN L, WANG Q, CHEN Y, MA Y, WANG D. Involvement of microRNA-133a in the protective effect of hydrogen sulfide against ischemia/reperfusion-induced endoplasmic reticulum stress and cardiomyocyte apoptosis. Pharmacology. 2019;103:1–9. doi: 10.1159/000492969. PubMed DOI

SIBAI BM, STELLA CL. Diagnosis and management of atypical preeclampsia-eclampsia. Am J Obstet Gynecol. 2009;200:481.e481–487. doi: 10.1016/j.ajog.2008.07.048. PubMed DOI

SONG T, YAO Y, WANG T, HUANG H, XIA H. Tanshinone IIA ameliorates apoptosis of myocardiocytes by up-regulation of miR-133 and suppression of caspase-9. Eur J Pharmacol. 2017;815:343–350. doi: 10.1016/j.ejphar.2017.08.041. PubMed DOI

STRASZEWSKI-CHAVEZ SL, ABRAHAMS VM, MOR G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev. 2005;26:877–897. doi: 10.1210/er.2005-0003. PubMed DOI

UCHIDA Y, CHIYOMARU T, ENOKIDA H, KAWAKAMI K, TATARANO S, KAWAHARA K, NISHIYAMA K, SEKI N, NAKAGAWA M. MiR-133a induces apoptosis through direct regulation of GSTP1 in bladder cancer cell lines. Urol Oncol. 2013;31:115–123. doi: 10.1016/j.urolonc.2010.09.017. PubMed DOI

XU C, HU Y, HOU L, JU J, LI X, DU N, GUAN X, LIU Z, ZHANG T, QIN W, SHEN N, BILAL MU, LU Y, ZHANG Y, SHAN H. β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J Mol Cell Cardiol. 2014;75:111–121. doi: 10.1016/j.yjmcc.2014.07.009. PubMed DOI

YANG H, HE X, WANG C, ZHANG L, YU J, WANG K. Knockdown of TUG 1 suppresses hypoxia-induced apoptosis of cardiomyocytes by up-regulating miR-133a. Arch Biochem Biophys. 2020;681:108262. doi: 10.1016/j.abb.2020.108262. PubMed DOI

YANG QS, JIANG LP, HE CY, TONG YN, LIU YY. Up-regulation of microRNA-133a inhibits the MEK/ERK signaling pathway to promote cell apoptosis and enhance radio-sensitivity by targeting EGFR in esophageal cancer in vivo and in vitro. J Cell Biochem. 2017;118:2625–2634. doi: 10.1002/jcb.25829. PubMed DOI

YIN Y, DU L, LI X, ZHANG X, GAO Y. miR-133a-3p suppresses cell proliferation, migration, and invasion and promotes apoptosis in esophageal squamous cell carcinoma. J Cell Physiol. 2019;234:12757–12770. doi: 10.1002/jcp.27896. PubMed DOI

YU L, LI D, LIAO QP, YANG HX, CAO B, FU G, YE G, BAI Y, WANG H, CUI N, LIU M, LI YX, LI J, PENG C, WANG YL. High levels of activin A detected in preeclamptic placenta induce trophoblast cell apoptosis by promoting nodal signaling. J Clin Endocrinol Metab. 2012;97:E1370–E1379. doi: 10.1210/jc.2011-2729. PubMed DOI

MicroRNA-206 Contributes to the Progression of Preeclampsia by Suppressing the Viability and Mobility of Trophocytes via the Inhibition of AGTR1