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Antihypertensive Activity of Egg White Protein Ovotransferrin-Derived Peptides

  • Author / Creator
    Majumder, Kaustav
  • Hypertension afflicts ~22% of Canadian adults and 80% of the Canadian population over the age of 65. Due to the inevitable side effects associated with drug use, there is increasing interest in developing functional foods or natural health products as an alternative for the prevention and management of hypertension. Bioactive peptides with inhibitory activity against angiotensin converting enzyme (ACE), a key enzyme for regulating blood pressure, may reduce blood pressure. Our previous study has identified three potent ACE inhibitory peptides, IRW (Ile-Arg-Trp), IQW (Ile-Gln-Trp) and LKP (Leu-Lys-Pro) from egg white protein ovotransferrin. The specific objectives of this thesis were to 1) evaluate the anti-inflammatory and anti-oxidant activities of these peptides on endothelial cells and to understand their structural requirements for these activities, 2) test their in vivo anti-hypertensive activities using spontaneously hypertensive rats (SHRs), and 3) explore the possible molecular mechanism of action of egg peptide through gene expression analysis. The anti-oxidant and anti-inflammatory activities were studied using human umbilical vein endothelial cells (HUVECs). IRW significantly inhibited tumor necrosis factor (TNF) stimulated expression of intercellular cell adhesion molecule-I (ICAM-1) and vascular cell adhesion molecule-I (VCAM-1). IQW and LKP, however, only inhibited the expression of ICAM-1 or VCAM-1, respectively. The anti-inflammatory activities of IRW and IQW were mediated differentially through transcription factor nuclear-kappa B (NF-κB). Both IRW and IQW exhibited anti-oxidant activity by reducing superoxide generation, whereas LKP did not show any effect. The structural integrity of these peptides (IRW and IQW) was essential for their activities, since dipeptides or the combination of their constituent amino acids did not exhibit the same effect. In vivo antihypertensive activity was studied in SHRs using the telemetric method. Oral administration of IRW, IQW, and LKP (15 mg/kg BW) significantly lowered mean arterial pressure (MAP) by 40, 19, and 30 mmHg, respectively, over a period of 18 days. IRW treatment led to decreased angiotensin II (Ang II) levels, restored nitric oxide (NO) dependent vasorelaxation, and decreased expression of inflammatory markers such as ICAM-1 and VCAM-1 as well as tissue fibrosis. Therefore, the antihypertensive effect of IRW was likely mediated through ACE inhibition, endothelial nitric oxide synthase, and anti-inflammatory properties. IQW and LKP treatments also reduced plasma Ang II level and restored NO-dependent vasorelaxation; however, only IQW treatment reduced ICAM-1 expression and nitrotyrosine levels in the arteries. The antihypertensive activities of IQW and LKP were likely mediated through similar pathways involving increased NO-mediated vasorelaxation and ACE inhibition, but only IQW reduced vascular inflammation and oxidative stress. Since IRW (at 15 mg/kg BW) exhibited the most pronounced anti-hypertensive, anti-inflammatory, and anti-oxidant activities compared to other two peptides, further transcriptomics study was used to delineate the molecular mechanism. The study revealed that IRW treatment could significantly modulate the gene expression in mesenteric artery. Interestingly, IRW treatment could significantly up-regulated the expression of angiotensin converting enzyme-2 (ACE-2), a vasodilatory enzyme of the renin-angiotensin system (RAS). Upregulation of ACE-2 reduces the hyperactivity of the RAS and reduces blood pressure. In addition, IRW could reduce the gene expression of pro-inflammatory adhesion molecules, ICAM-1 and VCAM-1 that further supported the anti-inflammatory activity of egg peptide. Thus the present study confirmed the anti-hypertensive activity of these three egg protein derived peptides. ACE inhibitory peptides were thought to function through the inhibition of ACE. Our study added new insights that the antihypertensive activity of these peptides could be due to anti-inflammation and antioxidant activities, restored NO-dependent vasodilation, and up-regulation of ACE-2. Findings from this study support the potential of egg protein derived peptides for uses in the prevention and management of hypertension.

  • Subjects / Keywords
  • Graduation date
    2015-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3GF0N486
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Agricultural, Food, and Nutritional Science
  • Specialization
    • Food Science and Technology
  • Supervisor / co-supervisor and their department(s)
    • Jianping Wu, Department of Agricultural, Food, and Nutritional Science, University of Alberta
  • Examining committee members and their departments
    • Yoshinori Mine, Department of Food Science, University of Guelph
    • Thava Vasanthan, Department of Agricultural, Food, and Nutritional Science, University of Alberta
    • Michael Gaenzle, Department of Agricultural, Food, and Nutritional Science, University of Alberta
    • Doug Korver, Department of Agricultural, Food, and Nutritional Science, University of Alberta
    • Sandra T. Davidge, Deptment of Obstetrics and Gynecology, University of Alberta