Bioavailability and Metabolism of Bioactive Peptide IRW with Angiotensin-Converting Enzyme 2 (ACE2) Upregulatory Activity in Spontaneously Hypertensive Rats

Abstract

Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) upregulator. This study aimed to investigate the pharmacokinetic characteristics of IRW and identify the metabolites contributing to its antihypertensive activity in spontaneously hypertensive rats (SHRs). Rats were administered 100 mg of IRW/kg of the body weight via an intragastric or intravenous route. The bioavailability (F %) was determined to be 11.7%, and the half-lives were 7.9 ± 0.5 and 28.5 ± 6.8 min for gavage and injection, respectively. Interestingly, significant blood pressure reduction was not observed until 1.5 h post oral administration, or 2 h post injection, indicating that the peptide's metabolites are likely responsible for the blood pressure-lowering activity. Time-course metabolomics revealed a significant increase in the level of kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased the level of ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered the blood pressure and upregulated aortic ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW's blood pressure-lowering effects.

Food-Derived Up-Regulators and Activators of Angiotensin Converting Enzyme 2: A Review

“…Therefore, we cannot dismiss the possible contribution of peptide fragments or their metabolites to the physiological effects in vivo , an aspect that could be validated through time-course metabolomics. By employing this method, kynurenine, a metabolite of the peptide IRW, was identified as the molecule partially responsible for the antihypertensive effects of IRW after its degradation and metabolism in SHRs . In addition, although several ACE2 activating peptides have been identified, further exploration of these peptides is warranted to establish a comprehensive database for future structural and activity studies.…”

“…By employing this method, kynurenine, a metabolite of the peptide IRW, was identified as the molecule partially responsible for the antihypertensive effects of IRW after its degradation and metabolism in SHRs. 148 In addition, although several ACE2 activating peptides have been identified, further exploration of these peptides is warranted to establish a comprehensive database for future structural and activity studies. This will facilitate the determinization of the specific structural requirements responsible for ACE2 activation and the development of a peptide with the highest ACE2 activity.…”