Bax mRNA Expression as A Potential Biomarker of Placental Apoptosis in Early-onset Preeclampsia

Muhammad Javedh Iqbal, Diah Rumekti Hadiati, Didik Setyo Heriyanto

Abstract


BACKGROUND: Early-onset preeclampsia is characterized by higher oxidative stress and apoptosis level than late-onset one. Studies comparing the expression of the Bcl-2 family protein in early and late-onset preeclampsia are still lacking and show inconclusive evidence. This study aimed to compare the expression of Bax and Bcl-2 messenger RNA (mRNA) as a biomarker of placental apoptosis between early-onset and late-onset preeclampsia.

METHODS: A cross-sectional study was conducted using formalin-fixed, paraffin-embedded preeclamptic placental samples and dividing them into early-onset and late-onset preeclampsia groups. Bax and Bcl-2 mRNA expressions were assessed using the quantitative real-time polymerase chain reaction method. Apoptosis was assessed through DNA fragmentation examination by the ligation-mediated real-time polymerase chain reaction method.

RESULTS: Thirty early-onset and 30 late-onset preeclamptic placental samples were included. The mean fold change Bax mRNA in early-onset was higher than in late-onset preeclampsia (6.02±3.59 vs. 2.82±1.97; p=0.00). The mean fold change Bcl-2 mRNA early-onset was not different from late-onset preeclampsia (31.20±17.94 vs. 31.01±27.60; p=0.98). The mean DNA fragmentation cycle threshold in early-onset preeclampsia was lower than in late-onset preeclampsia (28.07±0.64 vs. 30.63±0.96; p=0.00). A weak negative correlation exists between fold change Bax mRNA and DNA fragmentation cycle threshold (r=-0.30; p=0.02).

CONCLUSION: Bax mRNA showed significant correlation in DNA fragmentation compared to Bcl-2 mRNA; hence, might show more role in apoptotic pathway. Early-onset preeclampsia has higher Bax mRNA relative expression and apoptosis than late-onset preeclampsia. Therefore, Bax mRNA can be potential biomarker in early-onset preeclampsia.

KEYWORDS: mRNA, Bax, Bcl-2, apoptosis, DNA fragmentation, early-onset, preeclampsia


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Akbar MI, Kinanti H, Ernawati EE, Lestari P. Maternal and perinatal outcomes of early-onset and late-onset preeclampsia at a tertiary center hospital. J South Asian Fed Obstet Gynaecol. 2021; 13(5): 338–42, CrossRef.

Wantania J, Bakri S, Pandelaki K, Chalid M. Altered level of soluble fms-like tyrosine kinase 1 (sFlt1) and hypoxia inducible factor-1alpha (HIF-1alpha) in normotensive pregnancy and preeclampsia. Indones Biomed J. 2013; 5(2): 121–8, CrossRef.

Puspasari A, Enis RN, Herlambang H. Genetic variant of vascular endothelial growth factor (VEGF)-A rs699947 is associated with preeclampsia. Mol Cell Biomed Sci. 2022; 6(2): 70–6, CrossRef.

Hu R, Zhou S, Li X. Altered Bcl-2 and Bax expression is associated with cultured first-trimester human cytotrophoblasts apoptosis induced by hypoxia. Life Sci. 2006; 79(4): 351–5, CrossRef.

Can M, Guven B, Bektas S, Arikan I. Oxidative stress and apoptosis in preeclampsia. Tissue Cell. 2014; 46(6): 477–81, CrossRef.

Holland OJ, Cuffe JSM, Dekker Nitert M, Callaway L, Kwan Cheung KA, Radenkovic F, et al. Placental mitochondrial adaptations in preeclampsia associated with progression to term delivery. Cell Death Dis. 2018; 9(12): 1150, CrossRef.

Wójtowicz A, Zembala-Szczerba M, Babczyk D, Kołodziejczyk-Pietruszka M, Lewaczyńska O, Huras H. Early- and late-onset preeclampsia: a comprehensive cohort study of laboratory and clinical findings according to the new ISHHP criteria. Int J Hypertens. 2019; 2019: 1–9, CrossRef.

Tranquilli AL, Brown MA, Zeeman GG, Dekker G, Sibai BM. The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens An Int J Women’s Cardiovasc Heal. 2013; 3(1): 44–7, CrossRef.

Akbar MIA, Sari IM, Ernawati E, Aditiawarman A. Plasma level of umbilical cord hemeoxygenase-1 (HO-1) and neonatal outcome in early onset and late onset severe preeclampsia. Mol Cell Biomed Sci. 2019; 3(1): 54–9, CrossRef.

Staff AC. The two-stage placental model of preeclampsia: an update. J Reprod Immunol. 2019; 134–135: 1–10, CrossRef.

Hu XQ, Zhang L. Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: implications in drug development. Drug Discov Today. 2021; 26(11): 2754–73, CrossRef.

Teguh M, Karkata MK, Wirakusumah FF, Mose JC, Septiani L, Satari MH. Correlation between protein-with-molecular-weight-53 (P53), burkitt cell lymphoma 2 (Bcl-2), and fas ligand (FasL) and vascular-cell-adhesion-molecule-1 (VCAM-1) mRNA expression levels in a pathogenesis study of preeclampsia. Int J Integr Heal Sci. 2014; 2(1): 23–9, CrossRef.

Kovács P, Joó JG, Tamás V, Molnár Z, Burik-Hajas D, Bódis J, et al. The role of apoptosis in the complex pathogenesis of the most common obstetrics and gynaecology diseases. Physiol Int. 2020; 107(1): 106–19, CrossRef.

Gokalp-Ozkorkmaz E, Asir F, Basaran SO, Agacayak E, Sahin F, Kaya S, et al. Examination of Bcl-2 and Bax protein levels for determining the apoptotic changes in placentas with gestational diabetes and preeclampsia. Proceedings. 2018; 2(25): 1548, CrossRef.

Salakou S, Kardamakis D, Tsamandas AC, Zolota V, Apostolakis E, Tzelepi V, et al. Increased Bax/Bcl-2 ratio up-regulates Caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis. In Vivo. 2007; 21(1): 123–32, PMID.

De Falco M, De Luca L, Acanfora F, Cavallotti I, Cottone G, Laforgia V, et al. Alteration of the Bcl-2:Bax ratio in the placenta as pregnancy proceeds. Histochem J. 2001; 33(7): 421–5, CrossRef.

Giantari I. Perbandingan Ekspresi Protein Bcl-xl pada Sel Trofoblas Antara Preeklamsia Awitan Dini dengan Preeklamsia Awitan Lambat [Thesis]. Yogyakarta: Universitas Gadjah Mada; 2019.

Sidhajati RA. Perbandingan Ekspresi Protein Bak Sel Trofoblas pada Preeklamsia Awitan Dini dan Awitan Lambat [Thesis]. Yogyakarta: Universitas Gadjah Mada; 2022, article.

Ariyana M, Hadiati DR, Rachman IT, Dewajani Purnomosari. Bax expression of trophoblast cells did not differ between early and late-onset preeclampsia. Indones J Obstet Gynecol. 2021; 9(3): 126–9, CrossRef.

Sumawan H. Perbandingan Ekspresi Bcl-2 (B-cell lymphoma 2) Sel Trofoblas Plasenta Antara Preeklamsia Awitan Dini dan Awitan Lambat [Thesis]. Yogyakarta: Universitas Gadjah Mada; 2019.

Putra DMS. Perbandingan Ekspresi Protein P53 Sel Trophoblas Antara Preeklamsia Awitan Dini dengan Preeklamsia Awitan Lanjut [Thesis]. Yogyakarta: Universitas Gadjah Mada; 2019.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001; 25(4): 402–8, CrossRef.

Lim JJ, Lee J Il, Kim DH, Song SH, Kim HJ, Lee WS, et al. DNA fragmentation of human sperm can be detected by ligation-mediated real-time polymerase chain reaction. Fertil Steril. 2013; 100(6): 1564-1571.e5, CrossRef.

Mohammadpour-Gharehbagh A, Jahantigh D, Eskandari M, Sadegh MH, Nematollahi MH, Rezaei M, et al. Genetic and epigenetic analysis of the BAX and BCL2 in the placenta of pregnant women complicated by preeclampsia. Apoptosis. 2019; 24(3–4): 301–11, CrossRef.

Hung TH, Chen SF, Liou JD, Hsu JJ, Li MJ, Yeh YL, et al. BAX, BAK, and mitochondrial oxidants are involved in hypoxia-reoxygenation-induced apoptosis in human placenta. Placenta. 2008; 29(7): 565–83, CrossRef.

Marín R, Chiarello DI, Abad C, Rojas D, Toledo F, Sobrevia L. Oxidative stress and mitochondrial dysfunction in early-onset and late-onset preeclampsia. Biochim Biophys Acta - Mol Basis Dis. 2020; 1866: 165961, CrossRef.

Kasture V, Kale A, Randhir K, Sundrani D, Joshi S. Effect of maternal omega-3 fatty acids and vitamin E supplementation on placental apoptotic markers in rat model of early and late-onset preeclampsia. Life Sci. 2019; 239: 11703, CrossRef.

Vavina OV, Khodzhaeva ZS, Vyssokikh MY, Klimenchenko NI, Muminova KT, Tarasova NV, et al. Profound mitochondrial dysfunction leads to early onset preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2016; 206: e118, CrossRef.

Hooker DJ, Mobarok M, Anderson JL, Rajasuriar R, Gray LR, Ellett AM, et al. A new way of measuring apoptosis by absolute quantitation of inter-nucleosomally fragmented genomic DNA. Nucleic Acids Res. 2012; 40(15): e113, CrossRef.

Quinn KH, Lacoursiere DY, Cui L, Bui J, Parast MM. The unique pathophysiology of early-onset severe preeclampsia: role of decidual T regulatory cells. J Reprod Immunol. 2011; 91: 76–82, CrossRef.

Hadiati DR, Palupi A, Hakimi M, Haryana SM. Comparison of BCL-XL protein expression in placental trophoblast cells between pregnancy complicated by severe preeclampsia and normotensive pregnancy. J Med Sci. 2018; 50(01): 33–41, CrossRef.

Ray J, Jurisicova A, Caniggia I. IFPA Trophoblast Research Award Lecture: the dynamic role of BCL2 family members in trophoblast cell fate. Placenta. 2009; 30(Suppl.): 96–100, CrossRef.

Ashraf UM, Hall DL, Rawls AZ, Alexander BT. Epigenetic processes during preeclampsia and effects on fetal development and chronic health. Clin Sci. 2021; 135(19): 2307–27, CrossRef.

Meiliana A, Wijaya A. MicroRNAs in cardiometabolic diseases. Indones Biomed J. 2013; 5(2): 67–80, CrossRef.

Hayder H, O’Brien J, Nadeem U, Peng C. MicroRNAs: crucial regulators of placental development. Reproduction. 2018; 155(6): R259–71, CrossRef.

Li P, Guo W, Du L, Zhao J, Wang Y, Liu L, et al. microRNA-29b contributes to preeclampsia through its effects on apoptosis, invasion, and angiogenesis of trophoblast cells. Clin Sci. 2013; 124(1): 27–40, CrossRef.

Ding GC, Chen M, Wang YX, Rui C, Xu W, Ding HJ, et al. MicroRNA-128a-induced apoptosis in HTR-8/SVneo trophoblast cells contributes to preeclampsia. Biomed Pharmacother. 2016; 81: 63–70, CrossRef.

Guo M, Zhao X, Yuan X, Li P. Elevated microRNA-34a contributes to trophoblast cell apoptosis in preeclampsia by targeting BCL2. J Hum Hypertens. 2017; 31(12): 815–20, CrossRef.




DOI: https://doi.org/10.18585/inabj.v15i3.2336

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