Altered methylation and expression patterns of genes regulating placental nitric oxide pathway in patients with severe preeclampsia

Abstract

Pre-eclampsia is a common pregnancy disorder syndrome whose molecular mechanism is not clear. Nitric oxide (NO) is a key regulator of placentation. Reduction of NO has previously been associated with endothelial dysfunction in pre-eclamptic women. Therefore, we measured expression and methylation of some placental genes that were involved in NO pathway like named ARG II, PRMT1 and DDAH2 in pre-eclampsia and normal pregnancies in order to determine whether impairment of expression of these genes in the pre-eclamptic placenta could contribute to development of disease. ARG II, PRMT1 expressions as well as DDAH2 expression and methylation, in placentas collected from 59 patients with preeclampsia and 40 normotensive pregnancies were measured using real-time PCR and methylation specific PCR, respectively. The relationship among ARG II, PRMT1 and DDAH2 expressions was analyzed statistically. ARG II expression was increased, PRMT1 expression was not significantly changed. DDAH2 expression was decreased and qualitative methylation patterns were 32/59 and 21/40 in placentas from patients with pre-eclampsia compared with control group, respectively. The alterations in ARG II and DDAH2 expressions in pre-eclampsia patients maybe correlated with decreased eNOS expression. These findings indicate that ARG II and DDAH2 may be involved in pre-eclampsia pathogenesis and could be potential therapeutic targets for this disease.

Keywords

Preeclampsia ARG II PRMT1 DDAH2

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References

World Health Organization, WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia, 2011.

Grill

et al., Potential markers of preeclampsia – a review, Reproductive Biology and Endocrinology 7(70) (2009).

Dalmaz

Santos

Botton

Tedoldi

and Roisenberg

, Relationship between polymorphisms in thrombophilic genes and preeclampsia in a Brazilian population, Blood Cells, Molecules, and Diseases 37 (2006), 107–110.

Hill

L.D.

et al., Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia, PloS One 6 (2011), e16681.

Hladunewich

Karumanchi

S.A.

and Lafayette

, Pathophysiology of the clinical manifestations of preeclampsia, Clinical Journal of the American Society of Nephrology 2 (2007), 543–549.

Noris

Perico

and Remuzzi

, Mechanisms of disease: pre-eclampsia, Nature Reviews Nephrology 1 (2005), 98.

Johal

Lees

C.C.

Everett

T.R.

and Wilkinson

I.B.

, The nitric oxide pathway and possible therapeutic options in pre-eclampsia, British Journal of Clinical Pharmacology 78 (2014), 244–257.

Buhimschi

I.A.

Saade

G.R.

Chwalisz

and Garfield

R.E.

, The nitric oxide pathway in pre-eclampsia: pathophysiological implications, Human Reproduction Update 4 (1998), 25–42.

Sankaralingam

and Davidge

S.T.

, Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia, Cardiovascular Research 85 (2009), 194–203.

10.

Alpoim

P.N.

Godoi

L.C.

Freitas

L.G.

Gomes

K.B.

and Dusse

L.M.

, Assessment of L-arginine asymmetric 1 dimethyl (ADMA) in early-onset and late-onset (severe) preeclampsia, Nitric Oxide 33 (2013), 81–82.

11.

Vallance

and Leiper

, Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway, Arteriosclerosis, Thrombosis, and Vascular Biology 24 (2004), 1023–1030.

12.

Niu

P.-P.

et al., Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients, Journal of Translational Medicine 12 (2014), 170.

13.

Tamás

et al., L-arginine metabolism in early-onset and late-onset pre-eclamptic pregnancies, Scandinavian Journal of Clinical and Laboratory Investigation 73 (2013), 436–443.

14.

Leiper

and Nandi

, The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis, Nature reviews Drug Discovery 10 (2011), 277.

15.

Romero

, Clinical application of nitric oxide donors and blockers, Human Reproduction (Oxford, England) 13 (1998), 248–250.

16.

Alexander

J.M.

and Wilson

K.L.

, Hypertensive emergencies of pregnancy, Obstetrics and Gynecology Clinics of North America 40 (2013), 89–101.

17.

Bolte

A.C.

van Geijn

H.P.

and Dekker

G.A.

, Pharmacological treatment of severe hypertension in pregnancy and the role of serotonin2-receptor blockers, European Journal of Obstetrics and Gynecology and Reproductive Biology 95 (2001), 22–36.

18.

Noris

et al., L-arginine depletion in preeclampsia orients nitric oxide synthase toward oxidant species, Hypertension 43 (2004), 614–622.

19.

Prieto

et al., Hypoxia-reduced nitric oxide synthase activity is partially explained by higher arginase-2 activity and cellular redistribution in human umbilical vein endothelium, Placenta 32 (2011), 932–940.

20.

Siroen

M.P.

et al., No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia, Gynecologic and Obstetric Investigation 62 (2006), 7–13.

21.

Kim

et al., Reduced L-arginine level and decreased placental eNOS activity in preeclampsia, Placenta 27 (2006), 438–444.

22.

Maas

, Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA), Vascular Medicine 10 (2005), S49–S57.

23.

Alacam

et al., The role of asymmetric dimethyl arginine and oxidant/antioxidant system in preeclampsia, Fetal and Pediatric Pathology 30 (2011), 387–393.

24.

Anderssohn

et al., Severely decreased activity of placental dimethylarginine dimethylaminohydrolase in pre-eclampsia, European Journal of Obstetrics and Gynecology and Reproductive Biology 161 (2012), 152–156.

25.

Tomikawa

Fukatsu

Tanaka

and Shiota

, DNA methylation-dependent epigenetic regulation of dimethylarginine dimethylaminohydrolase 2 gene in trophoblast cell lineage, Journal of Biological Chemistry 281 (2006), 12163–12169.

26.

Jones

Tran

Leiper

Hingorani

and Vallance

, Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells, Biochemical and Biophysical Research Communications 310 (2003), 836–843.