Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Associations of cardiovascular risk with circulating peptides related to hypertensive disorders of pregnancy

Abstract

We previously identified seven peptides in serum that are associated with hypertensive disorders of pregnancy (HDP). However, the significance of these peptides in the general population is unknown. The aim of this study was to clarify the relationships of HDP-associated peptides with hypertension and other cardiovascular risks in adult men. We investigated the relationships of peptide levels with cardiovascular risk factors, including adiposity, blood pressure, blood lipids and glycemic status, in men (mean age: 46.4 years) who were receiving annual health checkups at their workplace. The concentrations of the abovementioned seven peptides in serum were measured simultaneously using a mass spectrometer. Among the seven peptides, only a peptide with m/z 2091 (P-2091) derived from fibrinogen-α showed a significant correlation with diastolic blood pressure (Spearman’s rank correlation coefficient [r], −0.446). Another peptide with m/z 2378 (P-2378) originating from complement component 4 showed a significant positive correlation with body mass index (r, 0.273) and a significant inverse correlation with HDL cholesterol (r, −0.336). In addition, a peptide with m/z 3156 (P-3156) derived from an inter-α-trypsin inhibitor showed significant inverse correlations with body mass index (r, −0.258) and triglycerides (r, −0.334). There was no significant correlation of the levels of any of the seven peptides with hemoglobin A1c. Among the seven peptides related to HDP, P-2091, P-2378 and P-3156 were inversely associated with diastolic blood pressure, HDL cholesterol and triglycerides, respectively. Therefore, these peptides are possible biomarkers for discriminating cardiovascular risk in a general population.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376:631–44.

    Article  Google Scholar 

  2. 2.

    Naderi S, Tsai SA, Khandelwal A. Hypertensive disorders of pregnancy. Curr Atheroscler Rep. 2017;19:15.

    Article  Google Scholar 

  3. 3.

    Araki Y, Yanagida M. Hypertensive disorders of pregnancy: strategy to develop clinical peptide biomarkers for more accurate evaluation of the pathophysiological status of this syndrome. Adv Clin Chem. 2020;94:1–30.

    CAS  Article  Google Scholar 

  4. 4.

    Tanaka K, Tsugawa N, Kim YO, Sanuki N, Takeda U, Lee LJ. A new rapid and comprehensive peptidome analysis by one-step direct transfer technology for 1-D electrophoresis/MALDI mass spectrometry. Biochem Biophys Res Commun. 2009;379:110–4.

    CAS  Article  Google Scholar 

  5. 5.

    Araki Y, Nonaka D, Tajima A, Maruyama M, Nitto T, Ishikawa H, et al. Quantitative peptidomic analysis by a newly developed one-step direct transfer technology without depletion of major blood proteins: its potential utility for monitoring of pathophysiological status in pregnancy-induced hypertension. Proteomics. 2011;11:2727–37.

    CAS  Article  Google Scholar 

  6. 6.

    Araki Y, Nonaka D, Hamamura K, Yanagida M, Ishikawa H, Banzai M, et al. Clinical peptidomic analysis by a one-step direct transfer technology: its potential utility for monitoring of pathophysiological status in female reproductive system disorders. J Obstet Gynaecol Res. 2013;39:1440–8.

    CAS  Article  Google Scholar 

  7. 7.

    Umesawa M, Kobashi G. Epidemiology of hypertensive disorders in pregnancy: prevalence, risk factors, predictors and prognosis. Hypertens Res. 2017;40:213–20.

    Article  Google Scholar 

  8. 8.

    Benschop L, Duvekot JJ, Roeters, van Lennep JE. Future risk of cardiovascular disease risk factors and events in women after a hypertensive disorder of pregnancy. Heart. 2019;105:1273–8.

    Article  Google Scholar 

  9. 9.

    Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275:1571–6.

    CAS  Article  Google Scholar 

  10. 10.

    Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–32.

    Article  Google Scholar 

  11. 11.

    Kampoli AM, Tousoulis D, Antoniades C, Siasos G, Stefanadis C. Biomarkers of premature atherosclerosis. Trends Mol Med. 2009;15:323–32.

    CAS  Article  Google Scholar 

  12. 12.

    Hamamura K, Nonaka D, Ishikawa H, Banzai M, Yanagida M, Nojima M, et al. Simple quantitation for potential serum disease biomarker peptides, primarily identified by a peptidomics approach in the serum with hypertensive disorders of pregnancy. Ann Clin Biochem. 2016;53:85–96.

    CAS  Article  Google Scholar 

  13. 13.

    Hamamura K, Yanagida M, Ishikawa H, Banzai M, Yoshitake H, Nonaka D, et al. Quantitative measurement of a candidate serum biomarker peptide derived from α2-HS-glycoprotein, and a preliminary trial of multidimensional peptide analysis in females with pregnancy-induced hypertension. Ann Clin Biochem. 2018;55:287–95.

    CAS  Article  Google Scholar 

  14. 14.

    Yanagida M, Hamamura K, Takamori K, Araki Y. The simultaneous quantification of candidate serum biomarker peptides for hypertensive disorders of pregnancy. Ann Clin Biochem. 2019;56:457–65.

    CAS  Article  Google Scholar 

  15. 15.

    Anonymous. Metabolic syndrome-definition and diagnostic criteria in Japan. J Jpn Soc Int Med. 2005;94:794–809.

    Article  Google Scholar 

  16. 16.

    Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, et al. Committee on the standardization of diabetes mellitus-related laboratory testing of Japan Diabetes Society. International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. J Diabetes Investig. 2012;3:39–40.

    Article  Google Scholar 

  17. 17.

    Wakabayashi I, Daimon T. The “cardiometabolic index” as a new marker determined by adiposity and blood lipids for discrimination of diabetes mellitus. Clin Chim Acta. 2015;438:274–8.

    CAS  Article  Google Scholar 

  18. 18.

    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    CAS  Article  Google Scholar 

  19. 19.

    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.

    CAS  Article  Google Scholar 

  20. 20.

    Hsieh SD, Muto T. Metabolic syndrome in Japanese men and women with special reference to the anthropometric criteria for the assessment of obesity: Proposal to use the waist-to-height ratio. Prev Med. 2006;42:135–9.

    Article  Google Scholar 

  21. 21.

    Flack JM, Adekola B. Blood pressure and the new ACC/AHA hypertension guidelines. Trends Cardiovasc Med. 2020;30:160–4.

    Article  Google Scholar 

  22. 22.

    Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. Japan Atherosclerosis Society. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan −2012 version. J Atheroscler Thromb. 2013;20:517–23.

    Article  Google Scholar 

  23. 23.

    Anonymous; American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62–9.

    Article  Google Scholar 

  24. 24.

    Musini VM, Wright JM. Factors affecting blood pressure variability: lessons learned from two systematic reviews of randomized controlled trials. PLoS ONE. 2009;4:e5673.

    Article  Google Scholar 

  25. 25.

    Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J. 1985;110:1100–7.

    CAS  Article  Google Scholar 

  26. 26.

    Gaziano JM, Hennekens CH, O’Donnell CJ, Breslow JL, Buring JE. Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation. 1997;96:2520–5.

    CAS  Article  Google Scholar 

  27. 27.

    Cordero A, Laclaustra M, León M, Casasnovas JA, Grima A, Luengo E, et al. MESYAS registry investigators. Comparison of serum lipid values in subjects with and without the metabolic syndrome. Am J Cardiol. 2008;102:424–8.

    CAS  Article  Google Scholar 

  28. 28.

    Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Relation of high TG-low HDL cholesterol and LDL cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen Male Study. Arterioscler Thromb Vasc Biol. 1997;17:1114–20.

    CAS  Article  Google Scholar 

  29. 29.

    Wakabayashi I, Marumo M, Kubota Y, Higashiyama A, Miyamoto Y, Okamura T. Cardiometabolic index as a useful discriminator for the risk of increased arterial stiffness. Clin Chim Acta. 2018;486:42–3.

    CAS  Article  Google Scholar 

  30. 30.

    Wakabayashi I, Sotoda Y, Hirooka S, Orita H. Association between cardiometabolic index and atherosclerotic progression in patients with peripheral arterial disease. Clin Chim Acta. 2015;446:231–6.

    CAS  Article  Google Scholar 

  31. 31.

    Copenhaver M, Yu CY, Hoffman RP. Complement components, C3 and C4, and the metabolic syndrome. Curr Diabetes Rev. 2019;15:44–8.

    CAS  Article  Google Scholar 

  32. 32.

    Copenhaver MM, Yu CY, Zhou D, Hoffman RP. Relationships of complement components C3 and C4 and their genetics to cardiometabolic risk in healthy, non-Hispanic white adolescents. Pediatr Res. 2020;87:88–94.

    CAS  Article  Google Scholar 

  33. 33.

    Fujita Y, Ezura Y, Emi M, Sato K, Takada D, Iino Y, et al. Hypercholesterolemia associated with splice-junction variation of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) gene. J Hum Genet. 2004;49:24–8.

    CAS  Article  Google Scholar 

  34. 34.

    Malaud E, Piquer D, Merle D, Molina L, Guerrier L, Boschetti E, et al. Carotid atherosclerotic plaques: proteomics study after a low-abundance protein enrichment step. Electrophoresis. 2012;33:470–82.

    CAS  Article  Google Scholar 

  35. 35.

    Moore PK, Hussaini I, Bhardwaj R. Cardiovascular effects of fibrinopeptide B. J Pharm Pharmacol. 1988;40:558–61.

    CAS  Article  Google Scholar 

  36. 36.

    Sturge J, Carey N, Davies AH, Powell JT. Fibrin monomer and fibrinopeptide B act additively to increase DNA synthesis in smooth muscle cells cultured from human saphenous vein. J Vasc Surg. 2001;33:847–53.

    CAS  Article  Google Scholar 

  37. 37.

    Hajri T, Caceres L, Angamarca-Armijos V. The burden of hypertension in Ecuador: a systematic review and meta-analysis. J Hum Hypertens. 2021;35:389–97.

    Article  Google Scholar 

  38. 38.

    Hata Y, Nakajima K. Life-style and serum lipids and lipoproteins. J Atheroscler Thromb. 2000;7:177–97.

    CAS  Article  Google Scholar 

  39. 39.

    Stevenson JC, Tsiligiannis S, Panay N. Cardiovascular risk in perimenopausal women. Curr Vasc Pharmacol. 2019;17:591–4.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (No. 21H03386) from the Japan Society for the Promotion of Science.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ichiro Wakabayashi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wakabayashi, I., Yanagida, M. & Araki, Y. Associations of cardiovascular risk with circulating peptides related to hypertensive disorders of pregnancy. Hypertens Res (2021). https://doi.org/10.1038/s41440-021-00747-6

Download citation

Keywords

  • Cardiovascular risk
  • Dyslipidemia
  • Hypertension
  • Mass spectrometry
  • Peptide biomarker
  • Pregnancy

Search

Quick links