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.

  • Article
  • Fast track – ISH2022 KYOTO
  • Published:

Pediatric dyslipidemia is associated with increased urinary ACE activity, blood pressure values, and carotidal-femoral pulse wave velocity

Hypertension Research volume 46, pages 1558–1569 (2023)Cite this article

Abstract

This study aimed to evaluate the enzymatic activity of the angiotensin-converting enzyme (ACE) in children and adolescents to investigate their relationship with dyslipidemia and other cardiometabolic alterations. Anthropometric measurements, blood pressure (BP), and fasting lipid concentrations were taken from 360 subjects. Categorization was done according to the levels of each lipoprotein (total cholesterol, triglycerides (TG), LDL-C, HDL-C, and non-HDL-C) into three groups: normolipidemic (NL), borderline (BL), and dyslipidemic (DL). Enzymatic activity in urine was measured using the substrates Z-FHL-OH and hippuryl-HL-OH (h-HL-OH) and the ACE activity ratio (Z-FHL-OH/h-HL-OH) was calculated. Dyslipidemic levels of HDL-C, TG, and LDL-C were observed in 23%, 9%, and 3% of the participants, respectively, and were more frequent in obese children (Chi-square, p < 0.001). ACE activity ratio was augmented in BL(HDL-C) when compared to NL(HDL-C) (5.06 vs. 2.39, p < 0.01), in DL(LDL-C) in comparison to BL(LDL-C) and NL(LDL-C) (8.7 vs. 1.8 vs. 3.0, p < 0.01), and in DL(non-HDL-C) than in BL(non-HDL-C) and in NL(non-HDL-C) (6.3 vs. 2.1 vs. 2.9, p = 0.02). The groups with impaired HDL-C and TG levels presented an increased diastolic BP percentile, and a higher systolic BP percentile was observed in BL(TG) and DL(TG). The carotidal-femoral pulse wave velocity (cfPWV) was higher in the groups with DL levels of TG and LDL-C than in NL groups. Hypertriglyceridemia was associated with higher cfPWV. No direct impact of the ACE activity on BP values was observed in this cohort, however, there was an association between hyperlipidemia and ACE upregulation which can trigger mechanisms driving to early onset of hypertension and cardiovascular disease.

Graphical abstract exemplifying the cohort, categorization of subjects into the groups NL normolipidemic, BL borderline, DL dyslipidemic, methods, and main findings. Pediatric dyslipidemia was consistent with dyslipidemia secondary to obesity (DSO), associated with higher urinary angiotensin-converting enzyme (ACE) activity ratio, BP blood pressure values, and carotidal-femoral pulse wave velocity (cfPWV).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Umer A, Kelley GA, Cottrell LE, Giacobbi P Jr, Innes KE, Lilly CL. Childhood obesity and adult cardiovascular disease risk factors: a systematic review with meta-analysis. BMC Public Health. 2017;17:683.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Caprio S, Santoro N, Weiss R. Childhood obesity and the associated rise in cardiometabolic complications. Nat Metab. 2020;2:223–32.

    Article  PubMed  PubMed Central  Google Scholar 

  3. NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet. 2017;390:2627–42.

    Article  Google Scholar 

  4. Moreira NF, Soares CDA, Junqueira TDS, Martins R. Tendências do estado nutricional de crianças no período de 2008 a 2015: dados do Sistema de Vigilância Alimentar e Nutricional (Sisvan). 2020;28:447–54.

  5. Radaelli G, Sausen G, Cesa CC, Portal VL, Pellanda LC. Secondary dyslipidemia in obese children - is there evidence for pharmacological treatment? Arq Bras Cardiol. 2018;111:356–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kennedy MJ, Jellerson KD, Snow MZ, Zacchetti ML. Challenges in the pharmacologic management of obesity and secondary dyslipidemia in children and adolescents. Paediatr Drugs. 2013;15:335–42.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institut. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128:S213–256.

    Article  PubMed Central  Google Scholar 

  8. Kwiterovich Jr PO. Clinical implications of the molecular basis of familial hypercholesterolemia and other inherited dyslipidemias. Circulation. 2011;123:1153–5.

  9. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2:247–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guang C, Phillips RD, Jiang B, Milani F. Three key proteases-angiotensin-I-converting enzyme (ACE), ACE2 and renin-within and beyond the renin-angiotensin system. Arch Cardiovasc Dis. 2012;105:373–85.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Singh BM, JLJAoim Mehta. Interactions between the renin-angiotensin system and dyslipidemia: relevance in the therapy of hypertension and coronary heart disease. Arch Intern Med. 2003;163:1296–304.

    Article  CAS  PubMed  Google Scholar 

  12. Keidar S, Attias J, Heinrich R, Coleman R, Aviram M. Angiotensin II atherogenicity in apolipoprotein E deficient mice is associated with increased cellular cholesterol biosynthesis. Atherosclerosis. 1999;146:249–57.

    Article  CAS  PubMed  Google Scholar 

  13. Liang B, Wang X, Yan F, Bian YF, Liu M, Bai R, et al. Angiotensin-(1-7) upregulates (ATP-binding cassette transporter A1) ABCA1 expression through cyclic AMP signaling pathway in RAW 264.7 macrophages. Eur Rev Med Pharmacol Sci. 2014;18:985–91.

    CAS  PubMed  Google Scholar 

  14. Yang HY, Bian YF, Xiao CS, Liang B, Zhang N, Gao F, et al. Angiotensin-(1-7) stimulates cholesterol efflux from angiotensin II-treated cholesterol-loaded THP-1 macrophages through the suppression of p38 and c-Jun N-terminal kinase signaling. Mol Med Rep. 2015;12:1387–92.

    Article  CAS  PubMed  Google Scholar 

  15. Yang BC, Phillips MI, Mohuczy D, Meng H, Shen L, Mehta P, et al. Increased angiotensin II type 1 receptor expression in hypercholesterolemic atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 1998;18:1433–9.

    Article  CAS  PubMed  Google Scholar 

  16. Li D, Saldeen T, Romeo F, Mehta JLJC. Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-κB. Circulation. 2000;102:1970–6.

    Article  CAS  PubMed  Google Scholar 

  17. Chen J, Li D, Schaefer R, Mehta JLJA. Cross-talk between dyslipidemia and renin–angiotensin system and the role of LOX-1 and MAPK in atherogenesis: Studies with the combined use of rosuvastatin and candesartan. Atherosclerosis. 2006;184:295–301.

    Article  CAS  PubMed  Google Scholar 

  18. Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res. 2014;114:1757–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol. 2012;302:H1219–1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Santos RA. Angiotensin-(1-7). Hypertension. 2014;63:1138–47.

    Article  CAS  PubMed  Google Scholar 

  21. Feltenberger JD, Andrade JM, Paraíso A, Barros LO, Filho AB, Sinisterra RD, et al. Oral formulation of angiotensin-(1–7) improves lipid metabolism and prevents high-fat diet-induced hepatic steatosis and inflammation in mice. Hypertension. 2013;62:324–30.

    Article  CAS  PubMed  Google Scholar 

  22. Yang HY, Bian YF, Zhang HP, Gao F, Xiao CS, Liang B, et al. Angiotensin-(1-7) treatment ameliorates angiotensin II-induced apoptosis of human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 2012;39:1004–10.

    Article  CAS  PubMed  Google Scholar 

  23. Daniels SR, Greer FR. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198–208.

    Article  PubMed  Google Scholar 

  24. Departamento Científico de Endócrinologia D Dislipidemia na criança e no adolescente - Orientações ao pediatra. https://www.sbp.com.br/fileadmin/user_upload/22336c-GPA_-_Dislipidemia_Crianca_e_Adoles.pdf.

  25. Oliosa PR, Zaniqueli D, Alvim RO, Barbosa MCR, Mill JG. Body fat percentage is better than indicators of weight status to identify children and adolescents with unfavorable lipid profile. J Pediatr (Rio J). 2019;95:112–8.

    Article  PubMed  Google Scholar 

  26. Center of disease control and prevention C. Defining childhood obesity. https://www.cdc.gov/obesity/childhood/defining.html. Accessed 10th June 2020.

  27. Ashwell M, Gibson S. Waist-to-height ratio as an indicator of ‘early health risk’: simpler and more predictive than using a ‘matrix’ based on BMI and waist circumference. BMJ Open. 2016;6:e010159.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Artigao L, Llavador J, Puras A, Abril L, Rubio M, Torres C, et al. Evaluation and validation of Omron Hem 705 CP and Hem 706/711 monitors for self-measurement of blood pressure. Aten Primaria. 2000;25:96–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zaniqueli D, Alvim RO, Luiz SG, Oliosa PR, de Sá Cunha R, Mill J. Ethnicity and arterial stiffness in children and adolescents from a Brazilian population. J Hypertens. 2017;35:2257–61.

    Article  CAS  PubMed  Google Scholar 

  31. Reference Values for Arterial Stiffness' Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31:2338–50.

    Article  Google Scholar 

  32. Hattori MA, Del Ben GL, Carmona AK, Casarini DE. Angiotensin I-converting enzyme isoforms (high and low molecular weight) in urine of premature and full-term infants. Hypertension. 2000;35:1284–90.

    Article  CAS  PubMed  Google Scholar 

  33. Piquilloud Y, Reinharz A, Roth M. Studies on the angiotensin converting enzyme with different substrates. Biochim Biophys Acta. 1970;206:136–42.

    Article  CAS  PubMed  Google Scholar 

  34. Friedland J, Silverstein E. A sensitive fluorimetric assay for serum angiotensin-converting enzyme. Am J Clin Pathol. 1976;66:416–24.

    Article  CAS  PubMed  Google Scholar 

  35. Children NHBPEPWGoHBPi, Pediatrics AJ. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555–76.

    Article  Google Scholar 

  36. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37:S81–S90.

  37. Kavey RE. Combined dyslipidemia in childhood. J Clin Lipidol. 2015;9:S41–56.

    Article  PubMed  Google Scholar 

  38. Rainwater DL, McMahan CA, Malcom GT, Scheer WD, Roheim PS, McGill HC Jr, et al. Lipid and apolipoprotein predictors of atherosclerosis in youth: apolipoprotein concentrations do not materially improve prediction of arterial lesions in PDAY subjects. The PDAY Research Group. Arterioscler Thromb Vasc Biol. 1999;19:753–61.

    Article  CAS  PubMed  Google Scholar 

  39. Turer CB, Brady TM, De Ferranti SD. Obesity, hypertension, and dyslipidemia in childhood are key modifiable antecedents of adult cardiovascular disease: a call to action. Circulation. 2018;137:1256–9.

  40. Halperin RO, Sesso HD, Ma J, Buring JE, Stampfer MJ, Michael Gaziano JJH. Dyslipidemia and the risk of incident hypertension in men. Hypertension. 2006;47:45–50.

    Article  CAS  PubMed  Google Scholar 

  41. Goldberg IJ, Eckel RH, McPherson RJA. Triglycerides and heart disease: still a hypothesis? thrombosis, biology v. 2011;31:1716–25.

    Article  CAS  Google Scholar 

  42. Campos H, Arnold KS, Balestra ME, Innerarity TL, Krauss RM. Differences in receptor binding of LDL subfractions. Arterioscler Thromb Vasc Biol. 1996;16:794–801.

    Article  CAS  PubMed  Google Scholar 

  43. Cook S, Kavey RE. Dyslipidemia and pediatric obesity. Pediatr Clin North Am. 2011;58:1363–73.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Fernandes FB, Fernandes AB, Febba ACS, Leite APO, Leite CA, Vitalle MSS, et al. Association of Ang-(1-7) and des-Arg(9)BK as new biomarkers of obesity and cardiometabolic risk factors in adolescents. Hypertens Res. 2021;44:969–77.

    Article  CAS  PubMed  Google Scholar 

  45. Sun Y, Goes Martini A, Janssen MJ, Garrelds IM, Masereeuw R, Lu X, et al. Megalin: a novel endocytic receptor for prorenin and renin. Hypertension. 2020;75:1242–50.

    Article  PubMed  Google Scholar 

  46. Ehlers MR, Gordon K, Sturrock E. Shedding the load of hypertension: the proteolytic processing of angiotensin-converting enzyme: forum-review. S Afr Med J. 2012;102:461–4.

    Article  CAS  PubMed  Google Scholar 

  47. Aragão DS, de Andrade MC, Ebihara F, Watanabe IK, Magalhães DC, Juliano MA, et al. Serine proteases as candidates for proteolytic processing of angiotensin-I converting enzyme. Int J Biol Macromol. 2015;72:673–9.

    Article  PubMed  Google Scholar 

  48. Casarini DE, Plavinik FL, Zanella MT, Marson O, Krieger JE, Hirata IY, et al. Angiotensin converting enzymes from human urine of mild hypertensive untreated patients resemble the N-terminal fragment of human angiotensin I-converting enzyme. Int J Biochem Cell Biol. 2001;33:75–85.

    Article  CAS  PubMed  Google Scholar 

  49. Roman RJ, Fan F, Zhuo JL. Intrarenal Renin–Angiotensin System: Locally Synthesized or Taken up Via Endocytosis? Hypertension. 2016,67:831–3.

  50. Williams TA, Danilov S, Alhenc-Gelas F, Soubrier FJBP. A study of chimeras constructed with the two domains of angiotensin I-converting enzyme. Biochem Pharmacol. 1996;51:11–4.

    Article  CAS  PubMed  Google Scholar 

  51. Deddish PA, Marcic B, Jackman HL, Wang HZ, Skidgel RA, Erdös EG. N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension. 1998;31:912–7.

    Article  CAS  PubMed  Google Scholar 

  52. Fernandes FB, Plavnik FL, Teixeira AM, Christofalo DM, Ajzen SA, Higa EM, et al. Association of urinary N-domain Angiotensin I-converting enzyme with plasma inflammatory markers and endothelial function. Mol Med. 2008;14:429–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Krauspenhar B, Sontag F, Ronchi FA, Casarini DE, Poli-de-Figueiredo CE, Pinheiro da Costa BE. Angiotensin converting enzyme 90 kDa isoform: biomarker for diagnosis of preeclampsia? Med Hypotheses. 2014;83:526–9.

    Article  CAS  PubMed  Google Scholar 

  54. Leite CA, Bertoncello NS, Watanabe IK, Fernandes FB, Andrade MC, Ronchi FA, et al. 90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model. J Bras Nefrol. 2017;39:11–4.

    Article  PubMed  Google Scholar 

  55. Maluf-Meiken LC, Fernandes FB, Aragão DS, Ronchi FA, Andrade MC, Franco MC, et al. N-domain isoform of Angiotensin I converting enzyme as a marker of hypertension: populational study. Int J Hypertens. 2012;2012:581780.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Siragy HM, Carey RM. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am J Nephrol. 2010;31:541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by São Paulo Research Foundation (FAPESP, processes 2018/16653-7 and 2017/17027-0). We appreciate the support from “Estação Conhecimento” during recruitment and data collection and we acknowledge “Fundação Vale” and the Foundation for support of research and innovation of Espírito Santo (FAPES, process 65854420/2014) for the financial support of Dr. José Mill research from which data and samples were collected and posteriorly used in the present study.

Author information

Authors and Affiliations

  1. Department of Medicine, Discipline of Nephrology, Federal University of São Paulo, São Paulo, Brazil

    Nayara Azinheira Nobrega Cruz, Lilian Caroline Gonçalves de Oliveira & Dulce Elena Casarini

  2. Center of Biological Sciences and Health, Mackenzie Presbyterian University, São Paulo, Brazil

    Fernanda Barrinha Fernandes

  3. Postgraduate Program in Public Health, Federal University of Espírito Santo, Vitória, Brazil

    Divanei dos Anjos Zaniqueli & Polyana Romano Oliosa

  4. Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil

    José Geraldo Mill

Authors
  1. Nayara Azinheira Nobrega Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lilian Caroline Gonçalves de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernanda Barrinha Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Divanei dos Anjos Zaniqueli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Polyana Romano Oliosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José Geraldo Mill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dulce Elena Casarini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dulce Elena Casarini.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cruz, N.A.N., de Oliveira, L.C.G., Fernandes, F.B. et al. Pediatric dyslipidemia is associated with increased urinary ACE activity, blood pressure values, and carotidal-femoral pulse wave velocity. Hypertens Res 46, 1558–1569 (2023). https://doi.org/10.1038/s41440-023-01240-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-023-01240-y

Keywords

This article is cited by

Search

Advanced search

Quick links