To evaluate the serum levels of the serine proteinase inhibitor kallistatin in women with preeclampsia (PE).
The clinical and laboratory parameters of 55 consecutive women with early-onset PE (EOPE) and 55 consecutive women with late-onset PE (LOPE) were compared with 110 consecutive gestational age (GA)-matched (±1 week) pregnant women with an uncomplicated pregnancy and an appropriate for gestational age fetus.
Mean serum kallistatin was significantly lower in women with PE compared to the GA-matched-controls (27.74±8.29 ng/mL vs. 37.86±20.64 ng/mL, p<0.001); in women with EOPE compared to that of women in the control group GA-matched for EOPE (24.85±6.65 ng/mL vs. 33.37±17.46 ng/mL, p=0.002); and in women with LOPE compared to that of women in the control group GA-matched for LOPE (30.87±8.81 ng/mL vs. 42.25±22.67 ng/mL, p=0.002). Mean serum kallistatin was significantly lower in women with EOPE compared to LOPE (24.85±6.65 ng/mL vs. 30.87±8.81 ng/mL, p<0.001). Serum kallistatin had negative correlations with systolic and diastolic blood pressure, creatinine, and positive correlation with GA at sampling and GA at birth.
Serum kallistatin levels are decreased in preeclamptic pregnancies compared to the GA-matched-controls. This decrease was also significant in women with EOPE compared to LOPE. Serum kallistatin had negative correlation with systolic and diastolic blood pressure, creatinine and positive correlation with GA at sampling and GA at birth.
We would like to thank our beloved nurse Medine Eltutan from our pregnancy outpatient clinic for her kind support and dedication during the patient recruitment.
Research funding: This study was financed by Istanbul Cerrahpasa University, Istanbul, Turkey, and Carl von Ossietzky University Oldenburg, University Hospital for Obstetrics and Gynecology in Klinikum Oldenburg AöR, Oldenburg, Germany.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study protocol was approved by the Ethics Committee of Istanbul Cerrahpasa University, School of Medicine and informed consent was obtained from all women participating our study. We have complied with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects and/or animals.
1. Poon, LC, Shennan, A, Hyett, JA, Kapur, A, Hadar, E, Divakar, H, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet 2019;145:1–33.https://doi.org/10.1002/ijgo.12802. Search in Google Scholar
3. Chao, J, Chai, KX, Chen, LM, Xiong, W, Chao, S, Woodley-Miller, C, et al. Tissue kallikrein-binding protein is a serpin. I. Purification, characterization, and distribution in normotensive and spontaneously hypertensive rats. J Biol Chem 1990;265:16394–401. Search in Google Scholar
4. Chen, VC, Chao, L, Chao, J. Reactive-site specificity of human kallistatin toward tissue kallikrein probed by site-directed mutagenesis. Biochim Biophys Acta 2000;1479:237–46. https://doi.org/10.1016/s0167-4838(00)00044-3. Search in Google Scholar
5. Chen, VC, Chao, L, Chao, J. Roles of the P1, P2, and P3 residues in determining inhibitory specificity of kallistatin toward human tissue kallikrein. J Biol Chem 2000;275:38457–66.https://doi.org/10.1074/jbc.m005605200. Search in Google Scholar
6. Chen, VC, Chao, L, Pimenta, DC, Bledsoe, G, Juliano, L, Chao, J. Identification of a major heparin-binding site in kallistatin. J Biol Chem 2001;276:1276–84.https://doi.org/10.1074/jbc.m005791200. Search in Google Scholar
8. Chao, J, Chao, L. Biochemistry, regulation and potential function of kallistatin. Biol Chem Hoppe Seyler 1995;376:705–13. Search in Google Scholar
9. Chen, LM, Song, Q, Chao, L, Chao, J. Cellular localization of tissue kallikrein and kallistatin mRNAs in human kidney. Kidney Int 1995;48:690–7.https://doi.org/10.1038/ki.1995.339. Search in Google Scholar
10. Wolf, WC, Harley, RA, Sluce, D, Chao, L, Chao, J. Localization and expression of tissue kallikrein and kallistatin in human blood vessels. J Histochem Cytochem 1999;47:221–8.https://doi.org/10.1177/002215549904700210. Search in Google Scholar
12. Chao, J, Miao, RQ, Chen, V, Chen, LM, Chao, L. Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. Biol Chem 2001;382:15–21.https://doi.org/10.1515/bc.2001.003. Search in Google Scholar
13. Gao, L, Yin, H, Smith R J, S., Chao, L, Chao, J. Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction. Lab Invest 2008;88:1157–66.https://doi.org/10.1038/labinvest.2008.85. Search in Google Scholar
14. Lin, WC, Chen, CW, Huang, YW, Chao, L, Chao, J, Lin, YS, et al. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep 2015;5:12463.https://doi.org/10.1038/srep12463. Search in Google Scholar
15. Chao, J, Schmaier, A, Chen, LM, Yang, Z, Kallistatin, CL. A novel human tissue kallikrein inhibitor: levels in body fluids, blood cells, and tissues in health and disease. J Lab Clin Med 1996;127:612–20.https://doi.org/10.1016/s0022-2143(96)90152-3. Search in Google Scholar
16. Stadnicki, A, Mazurek, U, Plewka, D, Wilczok, T. Intestinal tissue kallikrein-kallistatin profile in inflammatory bowel disease. Int Immunopharmacol 2003;3:939–44.https://doi.org/10.1016/s1567-5769(03)00054-7. Search in Google Scholar
17. Cheng, Z, Lv, Y, Pang, S, Bai, R, Wang, M, Lin, S, et al. Kallistatin, a new and reliable biomarker for the diagnosis of liver cirrhosis. Acta Pharm Sin B 2015;5:194–200.https://doi.org/10.1016/j.apsb.2015.02.003. Search in Google Scholar
18. Lin, WC, Lu, SL, Lin, CF, Chen, CW, Chao, L, Chao, J, et al. Plasma kallistatin levels in patients with severe community-acquired pneumonia. Crit Care 2013;17:R27.https://doi.org/10.1186/cc12507. Search in Google Scholar
19. Zhu, H, Chao, J, Kotak, I, Guo, D, Parikh, SJ, Bhagatwala, J, et al. Plasma kallistatin is associated with adiposity and cardiometabolic risk in apparently healthy African American adolescents. Metabolism 2013;62:642–6.https://doi.org/10.1016/j.metabol.2012.10.012. Search in Google Scholar
20. Maul, H, Longo, M, Saade, GR, Garfield, RE. Nitric oxide and its role during pregnancy: from ovulation to delivery. Curr Pharm Des 2003;9:359–80.https://doi.org/10.2174/1381612033391784. Search in Google Scholar
22. Schleussner, E, Lehmann, T, Kahler, C, Schneider, U, Schlembach, D, Groten, T. Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial. J Perinat Med 2014;42:507–14.https://doi.org/10.1515/jpm-2013-0212. Search in Google Scholar
23. Schleussner, E, Lehmann, T, Kahler, C, Schneider, U, Schlembach, D, Groten, T. Erratum to: impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial. J Perinat Med 2015;43:641.https://doi.org/10.1515/jpm-2015-0262. Search in Google Scholar
24. Ogge, G, Chaiworapongsa, T, Romero, R, Hussein, Y, Kusanovic, JP, Yeo, L, et al. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med 2011;39:641–52. https://doi.org/10.1515/jpm.2011.098. Search in Google Scholar
26. Arul Nambi Rajan, K, Khater, M, Soncin, F, Pizzo, D, Moretto-Zita, M, Pham, J, et al. Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. Placenta 2018;62:1–8. https://doi.org/10.1016/j.placenta.2017.12.002. Search in Google Scholar
27. Pham, J, Arul Nambi Rajan, K, Li, P, Parast, MM. The role of Sirtuin1-PPAR gamma axis in placental development and function. J Mol Endocrinol 2018;60:R201–12. https://doi.org/10.1530/jme-17-0315. Search in Google Scholar
28. Poidatz, D, Dos Santos, E, Duval, F, Moindjie, H, Serazin, V, Vialard, F, et al. Involvement of estrogen-related receptor-gamma and mitochondrial content in intrauterine growth restriction and preeclampsia. Fertil Steril 2015;104:483–90.https://doi.org/10.1016/j.fertnstert.2015.05.005. Search in Google Scholar
29. Yin, Y, Feng, Y, Zhao, H, Zhao, Z, Yua, H, Xu, J, et al. SIRT1 inhibits releases of HMGB1 and HSP70 from human umbilical vein endothelial cells caused by IL-6 and the serum from a preeclampsia patient and protects the cells from death. Biomed Pharmacother 2017;88:449–58.https://doi.org/10.1016/j.biopha.2017.01.087. Search in Google Scholar
30. Wang, Y, Lewis, DF, Gu, Y, Zhao, S, Groome, LJ. Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia. Hypertension 2011;57:336–42.https://doi.org/10.1161/hypertensionaha.110.163360. Search in Google Scholar
31. Zhao, S, Gu, Y, Dong, Q, Fan, R, Wang, Y. Altered interleukin-6 receptor, IL-6R and gp130, production and expression and decreased SOCS-3 expression in placentas from women with pre-eclampsia. Placenta 2008;29:1024–8.https://doi.org/10.1016/j.placenta.2008.09.011. Search in Google Scholar
32. Wang, Y, Dong, Q, Gu, Y, Groome, LJ. Up-regulation of miR-203 expression induces endothelial inflammatory response: potential role in preeclampsia. Am J Reprod Immunol 2016;76:482–90.https://doi.org/10.1111/aji.12589. Search in Google Scholar
33. Jabalie, G, Ahmadi, M, Koushaeian, L, Eghbal-Fard, S, Mehdizadeh, A, Kamrani, A, et al. Metabolic syndrome mediates proinflammatory responses of inflammatory cells in preeclampsia. Am J Reprod Immunol 2019;81:e13086.https://doi.org/10.1111/aji.13086. Search in Google Scholar
34. Morbidelli, L, Chang, CH, Douglas, JG, Granger, HJ, Ledda, F, Ziche, M. Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 1996;270:H411–5.https://doi.org/10.1152/ajpheart.1996.270.1.h411. Search in Google Scholar
35. He, H, Venema, VJ, Gu, X, Venema, RC, Marrero, MB, Caldwell, RB. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem1999; 274:25130–5.https://doi.org/10.1074/jbc.274.35.25130. Search in Google Scholar
36. Sha, Y, Zmijewski, J, Xu, Z, Abraham, E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 2008;180:2531–7.https://doi.org/10.4049/jimmunol.180.4.2531. Search in Google Scholar
37. Matias, ML, Romao, M, Weel, IC, Ribeiro, VR, Nunes, PR, Borges, VT, et al. Endogenous and uric acid-induced activation of NLRP3 inflammasome in pregnant women with preeclampsia. PLoS One 2015;10:e0129095.https://doi.org/10.1371/journal.pone.0129095. Search in Google Scholar
39. Chen, Q, Yin, YX, Wei, J, Tong, M, Shen, F, Zhao, M, et al. Increased expression of high mobility group box 1 (HMGB1) in the cytoplasm of placental syncytiotrophoblast from preeclamptic placentae. Cytokine 2016;85:30–6.https://doi.org/10.1016/j.cyto.2016.06.001. Search in Google Scholar
42. Chen, LM, Ma, J, Liang, YM, Chao, L, Chao, J. Tissue kallikrein-binding protein reduces blood pressure in transgenic mice. J Biol Chem 1996;271:27590–4.https://doi.org/10.1074/jbc.271.44.27590. Search in Google Scholar
43. Chen, LM, Chao, L, Chao, J. Adenovirus-mediated delivery of human kallistatin gene reduces blood pressure of spontaneously hypertensive rats. Hum Gene Ther 1997;8:341–7.https://doi.org/10.1089/hum.1997.8.3-341. Search in Google Scholar
44. Shen, B, Smith, RSJr., Hsu, YT, Chao, L, Chao, J. Kruppel-like factor 4 is a novel mediator of Kallistatin in inhibiting endothelial inflammation via increased endothelial nitric-oxide synthase expression. J Biol Chem 2009;284:35471–8.https://doi.org/10.1074/jbc.m109.046813. Search in Google Scholar
45. Guo, Y, Li, P, Bledsoe, G, Yang, ZR, Chao, L, Chao, J. Kallistatin inhibits TGF-beta-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res 2015;337:103–10.https://doi.org/10.1016/j.yexcr.2015.06.021. Search in Google Scholar
46. McMaster, WG, Kirabo, A, Madhur, MS, Harrison, DG. Inflammation, immunity, and hypertensive end-organ damage. Circ Res 2015;116:1022–33.https://doi.org/10.1161/circresaha.116.303697. Search in Google Scholar
47. Wang, CR, Chen, SY, Wu, CL, Liu, MF, Jin, YT, Chao, L, et al. Prophylactic adenovirus-mediated human kallistatin gene therapy suppresses rat arthritis by inhibiting angiogenesis and inflammation. Arthritis Rheum 2005;52:1319–24.https://doi.org/10.1002/art.20991. Search in Google Scholar
48. Chao, J, Yin, H, Yao, YY, Shen, B, Smith, RSJr., Chao, L. Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation. Hum Gene Ther 2006;17:1201–13.https://doi.org/10.1089/hum.2006.17.1201. Search in Google Scholar
49. Li, P, Guo, Y, Bledsoe, G, Yang, ZR, Fan, H, Chao, L, et al. Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis. Crit Care 2015;19:200.https://doi.org/10.1186/s13054-015-0919-4. Search in Google Scholar
50. Shen, B, Gao, L, Hsu, YT, Bledsoe, G, Hagiwara, M, Chao, L, et al. Kallistatin attenuates endothelial apoptosis through inhibition of oxidative stress and activation of Akt-eNOS signaling. Am J Physiol Heart Circ Physiol 2010;299:H1419–27.https://doi.org/10.1152/ajpheart.00591.2010. Search in Google Scholar
51. Liu, Y, Bledsoe, G, Hagiwara, M, Shen, B, Chao, L, Chao, J. Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am J Physiol Ren Physiol 2012;303:F1230–8.https://doi.org/10.1152/ajprenal.00257.2012. Search in Google Scholar
52. Chao, J, Guo, Y, Chao, L. Protective role of endogenous kallistatin in vascular injury and senescence by inhibiting oxidative stress and inflammation. Oxid Med Cell Longev 2018;2018:4138560.https://doi.org/10.1155/2018/4138560. Search in Google Scholar
The online version of this article offers supplementary material (https://doi.org/10.1515/jpm-2020-0142).
© 2021 Walter de Gruyter GmbH, Berlin/Boston