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Ameliorative effect of mussel-derived ACE inhibitory peptides on spontaneous hypertension rats

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Abstract

Purpose

The purpose of this study was to prepare the novel mussel-derived ACE inhibitory peptides (MEPs) by enzymatic hydrolysis of Mytilus edulis and investigate their antihypertensive effects in vivo.

Methods

After assessing the stability of MEPs in vitro, we investigated the effect of MEPs on hypertension using spontaneously hypertensive rats (SHRs). Subsequently, MEPs were purified and identified by ultrafiltration, gel filtration chromatography and liquid chromatography-tandem mass spectrometry (LC–MS/MS).

Results

Our study demonstrated that MEPs could keep stable ACE inhibitory activity after treatment with heat, acid, alkali, metal ions and simulated gastrointestinal digestive fluid. Additionally, the animal experiments showed that both short-term and long-term treatment with MEPs resulted in a significant reduction in systolic and diastolic blood pressure in SHRs. Mechanistically, the results suggested that MEPs could reduce vascular remodeling, regulate renin-angiotensin system (RAS), and inhibit kidney and myocardial fibrosis. Finally, we isolated and identified five peptides from MEPs, with the peptide Ile-Leu-Thr-Glu-Arg showed the highest ACE inhibition rate.

Conclusion

Our findings demonstrate the potential use of MEPs as active components in functional foods designed to lower blood pressure.

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Date availability

The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Afridi I, Canny J, Yao CH, Christensen B, Cooper RS, Kadiri S, Hill S, Kaplan N, Kuschnir E et al (2003) 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 21(11):1983–1992. https://doi.org/10.1097/01.hjh.0000084751-37215.d2

    Article  CAS  Google Scholar 

  2. Legese N, Tadiwos Y (2020) Epidemiology of hypertension in Ethiopia: a systematic review. Integrated Blood Pressure Control 13:135–143. https://doi.org/10.2147/ibpc.S276089

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lambert DW, Clarke NE, Turner AJ (2010) Not just angiotensinases: new roles for the angiotensin-converting enzymes. Cell Mol Life Sci 67(1):89–98. https://doi.org/10.1007/s00018-009-0152-x

    Article  CAS  PubMed  Google Scholar 

  4. Feng J, Dai Z, Zhang Y, Meng L, Ye J, Ma X (2015) Alteration of gene expression profile in kidney of spontaneously hypertensive rats treated with protein hydrolysate of blue mussel (Mytilus edulis) by DNA microarray analysis. PLoS One. https://doi.org/10.1371/journal.pone.0142016

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wijesekara I, Kim SK (2010) Angiotensin-I-Converting Enzyme (ACE) inhibitors from marine resources: prospects in the pharmaceutical industry. Mar Drugs 8(4):1080–1093. https://doi.org/10.3390/md8041080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Marinopoulou A, Petridis D (2021) A comparative study of the effect of different cooking methods on the quality and shucking of mussels. J Food Process Preserv. https://doi.org/10.1111/jfpp.15875

    Article  Google Scholar 

  7. Mititelu M, Neacsu SM, Oprea E, Dumitrescu DE, Nedelescu M, Draganescu D, Nicolescu TO, Rosca AC, Ghica M (2022) Black sea mussels qualitative and quantitative chemical analysis: nutritional benefits and possible risks through consumption. Nutrients 14(5):964–985. https://doi.org/10.3390/nu14050964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cunha SA, de Castro R, Coscueta ER, Pintado M (2021) Hydrolysate from Mussel Mytilus galloprovincialis meat: enzymatic hydrolysis. Optimiz Bioactive Propert Mol 26(17):17. https://doi.org/10.3390/molecules26175228

    Article  CAS  Google Scholar 

  9. Je JY, Park PJ, Byun HG, Jung WK, Kim SK (2005) Angiotensin I converting enzyme (ACE) inhibitory peptide derived from the sauce of fermented blue mussel Mytilus edulis. Bioresour Technol 96(14):1624–1629. https://doi.org/10.1016/j.biortech.2005.01.001

    Article  CAS  PubMed  Google Scholar 

  10. Wang J, Wang GL, Zhang YF, Zhang RG, Zhang YL (2022) Novel angiotensin-converting enzyme inhibitory peptides identified from walnut glutelin-1 hydrolysates: molecular interaction, stability, and antihypertensive effects. Nutrients 14(1):18. https://doi.org/10.3390/nu14010151

    Article  CAS  Google Scholar 

  11. Wang ZF, Shu GW, Chen L, Dai CJ, Yao CX, Zhang M, Dong X (2022) ACE inhibitory and antioxidant peptides from Alcalase-assisted Lactiplantibacillus plantarum L60 and Lacticaseibacillus rhamnosus LR22 fermentation of goat milk: optimization and identification. J Food Process Preserv 46(5):18. https://doi.org/10.1111/jfpp.16514

    Article  CAS  Google Scholar 

  12. Yin ZT, Yan RY, Jiang YS, Feng SB, Sun HL, Sun JY, Zhao DR, Li HH, Wang BW, Zhang N (2022) Identification of peptides in Qingke baijiu and evaluation of its angiotensin converting enzyme (ACE) inhibitory activity and stability. Food Chem 395:8. https://doi.org/10.1016/j.foodchem.2022.133551

    Article  CAS  Google Scholar 

  13. Charan JK, Kantharia ND (2013) How to calculate sample size in animal studies? J Pharmacol Pharmacother 4(4):303–306. https://doi.org/10.4103/0976-500X.119726

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sun XP, Wang M, Xu CJ, Wang SL, Li L, Zou SC, Yu J, Wei YX (2022) Positive effect of a pea-clam two-peptide composite on hypertension and organ protection in spontaneously hypertensive rats. Nutrients 14(19):18. https://doi.org/10.3390/nu14194069

    Article  CAS  Google Scholar 

  15. Lee SY, Hur SJ (2019) Purification of novel angiotensin converting enzyme inhibitory peptides from beef myofibrillar proteins and analysis of their effect in spontaneously hypertensive rat model. Biomed Pharmacother 116:7. https://doi.org/10.1016/j.biopha.2019.109046

    Article  CAS  Google Scholar 

  16. Oparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cifkova R, Dominiczak AF, Grassi G, Jordan J, Poulter NR, Rodgers A, Whelton PK (2018) Hypertension. Nat Rev Dis Primers 4:18014. https://doi.org/10.1038/nrdp.2018.14

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ma TQ, He LF, Luo Y, Li JC, Zhang GG, Cheng XJ, Bai YP (2022) Associations of baseline use of fish oil with progression of cardiometabolic multimorbidity and mortality among patients with hypertension: a prospective study of UK Biobank. Eur J Nutr 61(7):3461–3470. https://doi.org/10.1007/s00394-022-02889-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zheng YJ, Wang XY, Guo M, Yan XT, Zhuang YL, Sun Y, Li JR (2022) Two novel antihypertensive peptides identified in millet bran glutelin-2 hydrolysates: purification, in silico characterization, molecular docking with ACE and stability in various food processing conditions. Foods 11(9):15. https://doi.org/10.3390/foods11091355

    Article  CAS  Google Scholar 

  19. Zheng YJ, Shi PQ, Li Y, Zhuang YL, You LZ, Liu L, Wang W (2021) A novel ACE-inhibitory hexapeptide from camellia glutelin-2 hydrolysates: identification, characterization and stability profiles under different food processing conditions. Lwt-Food Sci Technol 147:8. https://doi.org/10.1016/j.lwt.2021.111682

    Article  CAS  Google Scholar 

  20. Wei Y, Liu Y, Li Y, Wang X, Zheng Y, Xu J, Sang S, Liu Y (2022) A novel antihypertensive pentapeptide identified in Quinoa Bran globulin hydrolysates purification, in silico characterization, molecular docking with ACE and stability against different food-processing conditions. Nutrients. https://doi.org/10.3390/nu14122420

    Article  PubMed  PubMed Central  Google Scholar 

  21. Quiros A, del Mar CM, Ramos M, Amigo L, Recio I (2009) Stability to gastrointestinal enzymes and structure-activity relationship of beta-casein-peptides with antihypertensive properties. Peptides 30(10):1848–1853. https://doi.org/10.1016/j.peptides.2009.06.031

    Article  CAS  PubMed  Google Scholar 

  22. Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27(3):282–293. https://doi.org/10.1253/jcj.27.282

    Article  CAS  PubMed  Google Scholar 

  23. Fuliang HU, Hepburn HR, Xuan HX, Chen ML, Daya S, Radloff SE (2005) Effects of propolis on blood glucose, blood lipid and free radicals in rats with diabetes mellitus. Pharmacol Res 51(2):147–152. https://doi.org/10.1016/j.phrs.2004.06.011

    Article  CAS  PubMed  Google Scholar 

  24. Xiao L, Tong X (2019) Advances in molecular mechanism of vascular remodeling in pulmonary arterial hypertension. Zhejiang da xue xue bao. Med Sci 48(1):102–110. https://doi.org/10.3785/j.issn.1008-9292.2019.02.15

    Article  Google Scholar 

  25. Brown I, Diederich L, Good ME, Delalio LJ, Murphy SA, Cortese-Krott MM, Hall JL, Le TH, Isakson BE (2018) Vascular smooth muscle remodeling in conductive and resistance arteries in hypertension. Arterioscler Thromb Vasc Biol 38(9):1969–1985. https://doi.org/10.1161/atvbaha.118.311229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lemarie CA, Tharaux PL, Lehoux S (2010) Extracellular matrix alterations in hypertensive vascular remodeling. J Mol Cell Cardiol 48(3):433–439. https://doi.org/10.1016/j.yjmcc.2009.09.018

    Article  CAS  PubMed  Google Scholar 

  27. Visentin S, Grumolato F, Nardelli GB, Di Camillo B, Grisan E, Cosmi E (2014) Early origins of adult disease: low birth weight and vascular remodeling. Atherosclerosis 237(2):391–399. https://doi.org/10.1016/j.atherosclerosis.2014.09.027

    Article  CAS  PubMed  Google Scholar 

  28. Liu XJ, Qiu J, Zhao SH, You BA, Ji X, Wang Y, Cui XP, Wang Q, Gao HQ (2012) Grape seed proanthocyanidin extract alleviates ouabain-induced vascular remodeling through regulation of endothelial function. Mol Med Rep 6(5):949–954. https://doi.org/10.3892/mmr.2012.1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Galderisi M, Divittis O (2008) Risk factor-induced cardiovascular remodeling and the effects of angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 51(6):523–531. https://doi.org/10.1097/FJC.0b013e31817751a7

    Article  CAS  PubMed  Google Scholar 

  30. Schiffrin EL (2005) Vascular endothelin in hypertension. Vascul Pharmacol 43(1):19–29. https://doi.org/10.1016/j.vph.2005.03.004

    Article  CAS  PubMed  Google Scholar 

  31. Giles TD (2006) Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J Clin Hypertens (Greenwich, Conn) 8(12 Suppl 4):2–16. https://doi.org/10.1111/j.1524-6175.2006.06023.x

    Article  CAS  Google Scholar 

  32. Chistiakov DA, Ashwell KW, Orekhov AN, Bobryshev YV (2015) Innervation of the arterial wall and its modification in atherosclerosis. Auton Neurosci-Basic Clin 193:7–11. https://doi.org/10.1016/j.autneu.2015.06.005

    Article  CAS  Google Scholar 

  33. Shibata S, Ishizawa K, Uchida S (2017) Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. Hypertens Res 40(3):221–225. https://doi.org/10.1038/hr.2016.137

    Article  CAS  PubMed  Google Scholar 

  34. Dong ZC, Dai HR, Feng ZD, Liu WB, Gao Y, Liu F, Zhang ZH, Zhang N, Dong X, Zhao QH, Zhou XS, Du JL, Liu BL (2021) Mechanism of herbal medicine on hypertensive nephropathy. Mol Med Rep 23(4):9. https://doi.org/10.3892/mmr.2021.11873

    Article  CAS  Google Scholar 

  35. Li QM, Chena HR, Zha XQ, Lu CQ, Pan LH, Luo JP (2018) Renoprotective effect of Chinese chive polysaccharides in adenine-induced chronic renal failure. Int J Biol Macromol 106:988–993. https://doi.org/10.1016/j.ijbiomac.2017.08.101

    Article  CAS  PubMed  Google Scholar 

  36. Zhu B-L, Ishikawa T, Michiue T, Tanaka S, Zhao D, Li D-R, Quan L, Oritani S, Maeda H (2007) Differences in postmortem urea nitrogen, creatinine and uric acid levels between blood and pericardial fluid in acute death. Leg Med (Tokyo) 9(3):115–122. https://doi.org/10.1016/j.legalmed.2006.10.002

    Article  CAS  PubMed  Google Scholar 

  37. Rosivall L (2009) Intrarenal renin-angiotensin system. Mol Cell Endocrinol 302(2):185–192. https://doi.org/10.1016/j.mce.2008.09.033

    Article  CAS  PubMed  Google Scholar 

  38. Wang J, He W, Guo LP, Zhang Y, Li H, Han SX, Shen DF (2017) The ACE2-Ang (1–7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction. Mol Med Rep 16(2):1973–1981. https://doi.org/10.3892/mmr.2017.6848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yu B, Chen H, Guo XQ, Hua H, Guan Y, Cui F, Tian YM, Zhang HX, Zhang XJ, Zhang Y, Ma HJ (2021) CIHH protects the heart against left ventricular remodelling and myocardial fibrosis by balancing the renin-angiotensin system in SHR. Life Sci 278:9. https://doi.org/10.1016/j.lfs.2021.119540

    Article  CAS  Google Scholar 

  40. Son M, Oh S, Choi J, Jang JT, Son KH, Byun K (2021) Attenuating effects of Dieckol on hypertensive nephropathy in spontaneously hypertensive rats. Int J Mol Sci. https://doi.org/10.3390/ijms22084230

    Article  PubMed  PubMed Central  Google Scholar 

  41. Strauss MH, Hall A (2007) Renin-angiotensin system and cardiovascular risk. Lancet 370(9581):23–24. https://doi.org/10.1016/s0140-6736(07)61034-4

    Article  PubMed  Google Scholar 

  42. Stegbauer J, Oberhauser V, Vonend O, Rump LC (2004) Angiotensin-(1–7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats. Cardiovasc Res 61(2):352–359. https://doi.org/10.1016/j.cardiores.2003.11.017

    Article  CAS  PubMed  Google Scholar 

  43. Oh GC, Cho HJ (2020) Blood pressure and heart failure. Clin Hyperten 26(1):8. https://doi.org/10.1186/s40885-019-0132-x

    Article  Google Scholar 

  44. Izzo JL, Gradman AH (2004) Mechanisms and management of hypertensive heart disease: from left ventricular hypertrophy to heart failure. Med Clin North Am 88(5):1257–1271. https://doi.org/10.1016/j.mcna.2004.06.002

    Article  PubMed  Google Scholar 

  45. Zhu T, Han QQ, Zhang XX, Hou QZ (2021) Effects of Xinnaoning combined with trimetazidine on the levels of CK and its isoenzymes, AST, ALT and LDH in patients with myocardial ischemia. Am J Transl Res 13(4):2875–2882

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Forner D, Kulai T, Arnason T, Gruchy SE, MacLeod M (2017) Ramipril-associated cholestasis in the setting of recurrent drug-induced liver injury. Gastroenterol Hepatol Bed Bench 10(2):143–146

    PubMed  PubMed Central  Google Scholar 

  47. Zhang J, Jin Z, Hu XX, Meng HM, Li J, Zhang XB, Liu HW, Deng TG, Yao S, Feng LL (2017) Efficient two-photon fluorescent probe for glutathione S-transferase detection and imaging in drug-induced liver injury sample. Anal Chem 89(15):8097–8103. https://doi.org/10.1021/acs.analchem.7b01659

    Article  CAS  PubMed  Google Scholar 

  48. Singh RR, Reindl KM (2021) Glutathione S-transferases in cancer. Antioxidants 10(5):25. https://doi.org/10.3390/antiox10050701

    Article  CAS  Google Scholar 

  49. Kaewsahnguan T, Noitang S, Sangtanoo P, Srimongkol P, Saisavoey T, Reamtong O, Choowongkomon K, Karnchanatat A (2021) A novel angiotensin I-converting enzyme inhibitory peptide derived from the trypsin hydrolysates of salmon bone proteins. PLoS One 16(9):32. https://doi.org/10.1371/journal.pone.0256595

    Article  CAS  Google Scholar 

  50. Sun SQ, Xu XT, Sun X, Zhang XQ, Chen XP, Xu NJ (2019) Preparation and identification of ACE inhibitory peptides from the marine macroalga Ulva intestinalis. Mar Drugs 17(3):17. https://doi.org/10.3390/md17030179

    Article  CAS  Google Scholar 

  51. Chen JL, Ryu B, Zhang YY, Liang P, Li CY, Zhou CX, Yang P, Hong PZ, Qian ZJ (2020) Comparison of an angiotensin-I-converting enzyme inhibitory peptide from tilapia (Oreochromis niloticus) with captopril: inhibition kinetics, in vivo effect, simulated gastrointestinal digestion and a molecular docking study. J Sci Food Agric 100(1):315–324. https://doi.org/10.1002/jsfa.10041

    Article  CAS  PubMed  Google Scholar 

  52. Lu X, Sun Q, Zhang LX, Wang RD, Gao JH, Jia C, Huang JN (2021) Dual-enzyme hydrolysis for preparation of ACE-inhibitory peptides from sesame seed protein: optimization, separation, and identification. J Food Biochem 45(4):18. https://doi.org/10.1111/jfbc.13638

    Article  CAS  Google Scholar 

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Acknowledgements

This study was financially supported by Qingdao key technology research and industrialization demonstration projects (22-3-3-hygg-5-hy).

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Authors

Contributions

Investigation, methodology, data analysis, validation, writing-original draft, QY; Methodology, data analysis, XS; Resources, validation, JC; Supervision, writing—review and editing, JY; Conceptualization, supervision, funding acquisition, writing—review and editing, YW. All authors: read and approved the final manuscript.

Corresponding authors

Correspondence to Jia Yu or Yuxi Wei.

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Conflict of interest

There are no conflicts of interest in this paper.

Ethical approval

This study was permitted by the Qingdao University Animal Protection and Use Ethics Committee (Animal Ethics Certificate NO.20210917SHR241020030) and the experimental procedures strictly conducted in compliance with the International Animal Protection Directive.

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The manuscript does not contain clinical studies or patient data.

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You, Q., Sun, X., Chen, J. et al. Ameliorative effect of mussel-derived ACE inhibitory peptides on spontaneous hypertension rats. Eur J Nutr 62, 3097–3111 (2023). https://doi.org/10.1007/s00394-023-03222-9

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