Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1

Zhou,Yiyuan; Zhang,Fang; Jiang,Huijiao; Xu,Di; Deng,Dongyang

doi:10.3892/etm.2021.10506

Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1

Authors:
- Yiyuan Zhou
- Fang Zhang
- Huijiao Jiang
- Di Xu
- Dongyang Deng
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Affiliations: Department of Obstetrics, The First Affliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550001, P.R. China
Published online on: July 28, 2021 https://doi.org/10.3892/etm.2021.10506
Article Number: 1072
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten‑eleven translocation 1 (TET1) expression, which subsequently increases calcium‑activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω‑Nitro‑L‑arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin‑eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription‑quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.

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1	Wang YA, Chughtai AA, Farquhar CM, Pollock W, Lui K and Sullivan EA: Increased incidence of gestational hypertension and preeclampsia after assisted reproductive technology treatment. Fertil Steril. 105:920–926.e2. 2016.PubMed/NCBI View Article : Google Scholar
2	Egeland GM, Klungsøyr K, Øyen N, Tell GS, Næss Ø and Skjærven R: Preconception cardiovascular risk factor differences between gestational hypertension and preeclampsia: Cohort Norway study. Hypertension. 67:1173–1180. 2016.PubMed/NCBI View Article : Google Scholar
3	Hua X, Zhang J, Guo Y, Shen M, Gaudet L, Janoudi G, Walker M and Wen SW: Effect of folic acid supplementation during pregnancy on gestational hypertension/preeclampsia: A systematic review and meta-analysis. Hypertens Pregnancy. 35:447–460. 2016.PubMed/NCBI View Article : Google Scholar
4	Hromadnikova I, Kotlabova K, Hympanova L and Krofta L: Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res. 137:126–140. 2016.PubMed/NCBI View Article : Google Scholar
5	Ripley TL and Saseen JJ: β-blockers: A review of their pharmacological and physiological diversity in hypertension. Ann Pharmacother. 48:723–733. 2014.PubMed/NCBI View Article : Google Scholar
6	Hu XQ, Dasgupta C, Chen M, Xiao D, Huang X, Han L, Yang S, Xu Z and Zhang L: Pregnancy reprograms large-conductance Ca²⁺-activated K⁺ channel in uterine arteries: Roles of ten-eleven translocation methylcytosine dioxygenase 1-mediated active demethylation. Hypertension. 69:1181–1191. 2017.PubMed/NCBI View Article : Google Scholar
7	Han YY, Wang LJ, Zhang L, Zhang WW, Ma KT, Li L and Si JQ: Association between potassium channel SNPs and essential hypertension in Xinjiang Kazak Chinese patients. Exp Ther Med. 14:1999–2006. 2017.PubMed/NCBI View Article : Google Scholar
8	Laukka T, Mariani CJ, Ihantola T, Cao JZ, Hokkanen J, Kaelin WG Jr, Godley LA and Koivunen P: Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J Biol Chem. 291:4256–4265. 2016.PubMed/NCBI View Article : Google Scholar
9	Wiehle L, Raddatz G, Musch T, Dawlaty MM, Jaenisch R, Lyko F and Breiling A: Tet1 and Tet2 protect DNA methylation canyons against hypermethylation. Mol Cell Biol. 36:452–461. 2015.PubMed/NCBI View Article : Google Scholar
10	Choudhury SR, Cui Y, Lubecka K, Stefanska B and Irudayaraj J: CRISPR-dCas9 mediated TET1 targeting for selective DNA demethylation at BRCA1 promoter. Oncotarget. 7:46545–46556. 2016.PubMed/NCBI View Article : Google Scholar
11	Thomson JP, Ottaviano R, Unterberger EB, Lempiäinen H, Muller A, Terranova R, Illingworth RS, Webb S, Kerr AR, Lyall MJ, et al: Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer. Cancer Res. 76:3097–3108. 2016.PubMed/NCBI View Article : Google Scholar
12	Somineni HK, Zhang X, Biagini Myers JM, Kovacic MB, Ulm A, Jurcak N, Ryan PH, Khurana Hershey GK and Ji H: Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution. J Allergy Clin Immunol. 137:797–805.e5. 2016.PubMed/NCBI View Article : Google Scholar
13	Zhu X, Girardo D, Govek EE, John K, Mellén M, Tamayo P, Mesirov JP and Hatten ME: Role of Tet1/3 genes and chromatin remodeling genes in cerebellar circuit formation. Neuron. 89:100–112. 2016.PubMed/NCBI View Article : Google Scholar
14	Pei YF, Tao R, Li JF, Su LP, Yu BQ, Wu XY, Yan M, Gu QL, Zhu ZG and Liu BY: TET1 inhibits gastric cancer growth and metastasis by PTEN demethylation and re-expression. Oncotarget. 7:31322–31335. 2016.PubMed/NCBI View Article : Google Scholar
15	Du C, Zheng Z, Li D, Chen L, Li N, Yi X, Yang Y, Guo F, Liu W, Xie X, et al: BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK. Oncotarget. 7:40174–40188. 2016.PubMed/NCBI View Article : Google Scholar
16	Friedman D, Kannan K, Faustin A, Shroff S, Thomas C, Heguy A, Serrano J, Snuderl M and Devinsky O: Cardiac arrhythmia and neuroexcitability gene variants in resected brain tissue from patients with sudden unexpected death in epilepsy (SUDEP). NPJ Genom Med. 3(9)2018.PubMed/NCBI View Article : Google Scholar
17	Díaz-Villamarín X, Dávila-Fajardo CL, Gónzalez-Medina MD, Soto-Pino MJ, Sánche-Gómez E, Acuña A, Gómez-Martín A, Martínez-González LJ, Casas-Hidalgo I and Cabeza-Barrera J: PKP-022 The KCNMB1 (A >G) (RS703505) genetic variant and the efficacy of tocilizumab in rheumatoid arthritis patients. Eur J Hosp Pharm Sci Pract. 23 (Suppl 1)(A188)2016.
18	Hu XQ, Chen M, Dasgupta C, Xiao D, Huang X, Yang S and Zhang L: Chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca²⁺-activated K⁺ channel function in ovine uterine arteries. Biol Reprod. 96:424–434. 2017.PubMed/NCBI View Article : Google Scholar
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
20	Jin S, Teng X, Xiao L, Xue H, Guo Q, Duan X, Chen Y and Wu Y: Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway. Exp Biol Med (Maywood). 242:1831–1841. 2017.PubMed/NCBI View Article : Google Scholar
21	Bogodvid TK, Andrianov VV, Muranova LN and Gainutdinov KL: Influence of nonspecific inhibitor of NO-synthase L-NAME on electric characteristics of premotor interneurons of terrestrial snails. Bionanoscience. 8:884–887. 2018.
22	Godbole SS, Kaul R, D'Souza SF and Nadkarni GB: Immobilization of fumarase by entrapment of rat liver mitochondria in polyacrylamide gel using gamma rays. Biotechnol Bioeng. 25:217–224. 1983.PubMed/NCBI View Article : Google Scholar
23	Kirchgessner M, Roth FX, Tschierschwitz A and Grassmann E: Nutritive effect of fumaric acid on growth and body composition of rats. Z Tierphysiol Tierernähr Futtermittelkd. 47:175–186. 1982.PubMed/NCBI(In German).
24	Kang J, Lienhard M, Pastor WA, Chawla A, Novotny M, Tsagaratou A, Lasken RS, Thompson EC, Surani MA, Koralov SB, et al: Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis. Proc Natl Acad Sci USA. 112:E4236–E4245. 2015.PubMed/NCBI View Article : Google Scholar
25	Yang GX, Fu HJ, Liu TW, Li JL, Shen Y and Qian J: Effects of atorvastatin on VSMC apoptosis in rabbits with atherosclerosis and its molecular mechanism. Chin J Arterioscler. 25:463–466. 2017.
26	Wang LJ, Zhang WW, Qian YF, Zhang L, Zhao L, Ma KT, Li L and Si JQ: Association between KCNMB1 polymorphism and essential hypertension in Xinjiang Kazak population. J Xian Jiaotong Univ. 37:78–81. 2016.