Food-derived angiotensin-converting enzyme inhibitory (ACEi) peptides have gained substantial interest as potential alternatives to synthetic drugs in the management of hypertension. Peptide size and sequence are two critical factors that determine their potency, bioavailability, and cellular mechanisms. Molecular interaction studies between ACE and ACEi peptides support that potent ACEi peptides are generally composed of hydrophobic, positively charged, and aromatic or cyclic amino acid residues at the third, second, and first position from the C-terminus, respectively. Small peptides containing N-terminal Tyr and/or C-terminal Pro could improve their stability against enterocyte peptidases and, thus, their bioavailability. Different ACEi peptides can reduce aberrant cellular proliferation, excessive inflammation, and oxidative stress but through different mechanisms. Further understanding the structure-activity-bioavailability relationships will help design novel potent ACEi peptides with improved bioavailability and in vivo efficacy. Practical applicationsAngiotensin-converting enzyme inhibitory peptides have the potential for uses as functional food ingredients against hypertension. K E Y W O R D S angiotensin-converting enzyme, angiotensin-converting enzyme inhibitory peptides, bioavailability, cellular mechanisms, molecular docking, vascular endothelial cells, vascular smooth muscle cells J Food Biochem. 2019;43:e12572.

Scope It is found in the previous study that egg‐white‐derived antihypertensive peptide Ile‐Arg‐Trp (IRW) upregulated angiotensin converting enzyme 2 (ACE2) in spontaneously hypertensive rats (SHRs). The objective of this study is to evaluate the contribution of ACE2 activation by IRW to blood‐pressure‐lowering activity in vivo. Methods and results Adult male SHRs (13–15 week old) are assigned into four groups: 1) untreated with saline infusion; 2) IRW administration (15 mg per kg body weight) with saline infusion; 3) Mas receptor (MasR) antagonist A779 (48 µg per kg body weight per h) infusion; 4) A779 infusion and IRW. Animals are implanted with telemetry transmitter first, and then an osmotic pump filled with saline or A779 is implanted. A779/saline is infused for 7 days, continued with an additional 7 days of treatments. Results indicate that blocking MasR abolished the blood‐pressure‐lowering effect of IRW. Akt/eNOS signaling in aorta is upregulated by IRW treatment but deactivated by A779 infusion. Circulating levels of interleukin 6 and monocyte chemoattractant protein 1, along with cyclooxygenase 2 in aorta are reduced by IRW but restored by A779 infusion. Conclusion IRW reduces blood pressure of SHR via the ACE2/Ang (1‐7)/MasR axis. Mechanisms pertaining to IRW as an ACE2 activator in vivo include enhanced endothelium‐dependent vasorelaxation and reduced vascular inflammation.

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The renin angiotensin system (RAS) is a key mediator of blood pressure regulation. Angiotensin II (Ang II), the active component of RAS, is a potent vasoconstrictor that also causes abnormal proliferation, oxidative stress, and inflammation in vascular smooth muscle cells (VSMCs) that contribute to atherosclerotic changes. Egg white ovotransferrin-derived tripeptide IRW (Ile-Arg-Trp) was previously shown to exert antihypertensive effect by reducing Ang II synthesis as well as endothelial cell inflammation and endothelial dysfunction. However, the effects of IRW on VSMCs are still unclear. In the present study, we evaluated the antiproliferative, antioxidant, and anti-inflammatory effects of IRW on VSMCs in the presence of Ang II stimulation. It was found that IRW treatment could attenuate Ang II-stimulated proliferation, superoxide production, and inflammation in VSMCs. These beneficial effects appeared to involve modulation of the NF-κB pathway. These findings could further our understanding on the antihypertensive mechanism of IRW beyond vascular endothelium.