Circulating Tissue Inhibitor of Metalloproteinase-4 levels are not a Predictor of Preeclampsia in the period between 20 and 25 Weeks of Gestation

Abstract

Objective To evaluate whether the circulating level of tissue inhibitor of metalloproteinase-4 (TIMP-4) in the period between 20 and 25 weeks of gestation is a predictor of preeclampsia.

Methods We have performed a case-control study, nested in a prospective study cohort in Ribeirão Preto, in the state of São Paulo, Brazil. Of the 1,400 pregnant women evaluated between 20 and 25 weeks of gestation, 460 delivered in hospitals outside of our institution. Of the 940 pregnant women who completed the protocol, 30 developed preeclampsia. Healthy pregnant women (controls, n = 90) were randomly selected from the remaining 910 participants. From blood samples collected between 20 and 25 weeks of gestation, we performed a screening of 55 angiogenesis-related proteins in 4 cases and 4 controls. The protein TIMP-4 was the most differentially expressed between cases and controls. Therefore, we measured this protein in all cases (n = 30) and controls selected (n = 90).

Results There were no differences in the plasma TIMP-4 levels of cases compared with controls (1,144 ± 263 versus 1,160 ± 362 pg/mL, respectively; p > 0.05).

Conclusion Plasma TIMP-4 levels were not altered at 20 to 25 weeks of gestation, before the manifestation of clinical symptoms; therefore, they are not good predictors of the development of preeclampsia.

Resumo

Objetivo Avaliar se o nível de inibidor tecidual de metaloproteinases tipo-4 (TIMP-4, na sigla em inglês) circulante no período entre 20 e 25 semanas de gestação é um preditor de preeclâmpsia.

Métodos Foi realizado um estudo caso-controle aninhado em uma coorte de estudo prospectivo em Ribeirão Preto, São Paulo, Brasil. De 1.400 mulheres grávidas avaliadas entre 20 e 25 semanas de gestação, 460 tiveram parto em hospitais fora da nossa instituição. Das 940 gestantes que completaram o protocolo, 30 desenvolveram preeclâmpsia. Gestantes saudáveis (controles, n = 90) foram selecionadas aleatoriamente das 910 participantes restantes. A partir de amostras de sangue coletadas entre 20 e 25 semanas de gestação, foi realizada uma triagem de 55 proteínas relacionadas à angiogênese em 4 casos e 4 controles. A proteína TIMP-4 foi a mais diferentemente expressa entre os casos e os controles; portanto, medimos esta proteína em todos os casos (n = 30) e controles selecionados (n = 90).

Resultados Não houve diferenças nos níveis plasmáticos de TIMP-4 nos casos em comparação com os controles (1.144 ± 263 versus 1.160 ± 362 pg/mL, respectivamente; p > 0,05).

Conclusão Os níveis plasmáticos de TIMP-4 não foram alterados no período entre 20 e 25 semanas de gestação antes da manifestação dos sintomas clínicos; portanto, não são um bom preditor do desenvolvimento da preeclâmpsia.

Keywords

preeclampsia - TIMP-4 - TIMPs - MMPs - prediction - circulating biomarkers - angiogenic biomarkers

Palavras-chave

preeclâmpsia - TIMP-4 - TIMPs - MMPs - predição - biomarcadores circulantes - biomarcadores angiogênicos

Contributors

Machado M. performed the ELISA analysis, Palei A. C. performed the protein array, Sandrim V. C. designed the study, performed the statistical analysis and drafted the manuscript. Bettiol H., Barbieri M. A, Cardoso V. C. and Cavalli R. C. designed and performed the BRISA study. All of the authors revised the final manuscript.

• References

• 1 Levine RJ, Maynard SE, Qian C. , et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350 (07) 672-683 Doi: 10.1056/NEJMoa031884
• 2 Maged AM, Saad H, Meshaal H. , et al. Maternal serum homocysteine and uterine artery Doppler as predictors of preeclampsia and poor placentation. Arch Gynecol Obstet 2017; 296 (03) 475-482 Doi: 10.1007/s00404-017-4457-y
• 3 Rocha-Penha L, Bettiol H, Barbieri MA, Cardoso VC, Cavalli RC, Sandrim VC. Myeloperoxidase is not a good biomarker for preeclampsia prediction. Sci Rep 2017; 7 (01) 10257 Doi: 10.1038/s41598-017-09272-4
• 4 Lind Malte A, Uldbjerg N, Wright D, Tørring N. Prediction of severe pre-eclampsia/HELLP syndrome by combination of sFlt-1, CT-pro-ET-1 and blood pressure: exploratory study. Ultrasound Obstet Gynecol 2018; 51 (06) 768-774 Doi: 10.1002/uog.17561
• 5 Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol 2011; 31 (01) 33-46 Doi: 10.1016/j.semnephrol.2010.10.004
• 6 Maynard SE, Min JY, Merchan J. , et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111 (05) 649-658 Doi: 10.1172/JCI17189
• 7 Schrey-Petersen S, Stepan H. Anti-angiogenesis and Preeclampsia in 2016. Curr Hypertens Rep 2017; 19 (01) 6 Doi: 10.1007/s11906-017-0706-5
• 8 Wathén KA, Ylikorkala O, Andersson S, Alfthan H, Stenman UH, Vuorela P. Maternal serum endostatin at gestational weeks 16-20 is elevated in subsequent pre-eclampsia but not in intrauterine growth retardation. Acta Obstet Gynecol Scand 2009; 88 (05) 593-598 Doi: 10.1080/00016340902838293
• 9 Hirokoshi K, Maeshima Y, Kobayashi K. , et al. Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia. Nephron Clin Pract 2007; 106 (01) c43-c50 Doi: 10.1159/000101483
• 10 da Silva AAM, Simões VMF, Barbieri MA. , et al. A protocol to identify non-classical risk factors for preterm births: the Brazilian Ribeirão Preto and São Luís prenatal cohort (BRISA). Reprod Health 2014; 11 (01) 79 Doi: 10.1186/1742-4755-11-79
• 11 American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131 Doi: 10.1097/01.AOG.0000437382.03963.88
• 12 Sandrim VC, Diniz S, Eleuterio NM, Gomes KB, Dusse LMS, Cavalli RC. Higher levels of circulating TIMP-4 in preeclampsia is strongly associated with clinical parameters and microRNA. Clin Exp Hypertens 2018; 40 (07) 609-612 Doi: 10.1080/10641963.2017.1411499
• 13 Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69 (03) 562-573 Doi: 10.1016/j.cardiores.2005.12.002
• 14 Melendez-Zajgla J, Del Pozo L, Ceballos G, Maldonado V. Tissue inhibitor of metalloproteinases-4. The road less traveled. Mol Cancer 2008; 7: 85 Doi: 10.1186/1476-4598-7-85
• 15 Koskivirta I, Rahkonen O, Mäyränpää M. , et al. Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology. Histochem Cell Biol 2006; 126 (03) 335-342 Doi: 10.1007/s00418-006-0163-8
• 16 Zile MR, Desantis SM, Baicu CF. , et al. Plasma biomarkers that reflect determinants of matrix composition identify the presence of left ventricular hypertrophy and diastolic heart failure. Circ Heart Fail 2011; 4 (03) 246-256 Doi: 10.1161/CIRCHEARTFAILURE.110.958199
• 17 Zhang Y, Ma Q, Yang H, Long Y, Liu X, Zhou C. Maternal plasma TIMP-4 levels combined with clinical risk factors for the early prediction of pregnancy-induced hypertension. Arch Gynecol Obstet 2015; 292 (05) 1043-1050 Doi: 10.1007/s00404-015-3753-7
• 18 Bigg HF, Shi YE, Liu YE, Steffensen B, Overall CM. Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2. J Biol Chem 1997; 272 (24) 15496-15500 Doi: 10.1074/jbc.272.24.15496
• 19 Zhang J, Cao YJ, Zhao YG, Sang QXA, Duan EK. Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3. Mol Hum Reprod 2002; 8 (07) 659-666 Doi: 10.1093/molehr/8.7.659