Hazelnut-Derived Peptide YYLLVR Improves Endothelial Dysfunction in Hypertension by Activating ACE2

This research aimed to investigate the antihypertensive effects of YYLLVR, a peptide derived from hazelnut, to improve endothelial dysfunction in spontaneously hypertensive rats (SHRs). YYLLVR decreased systolic blood pressure by 53.48 mmHg and diastolic blood pressure by 37.57 mmHg in SHRs and increased ACE2 expression by 2-fold (P < 0.05). It inhibited the ACE/Ang II/AGTR1 axis and promoted the ACE2/Ang-(1-7)/MAS axis (P < 0.05). In addition, YYLLVR increased the expression of NO and eNOS, inhibited the expression of ET-1 and iNOS expression, and reduced aortic thickness (P < 0.05). NO secretion and ACE2 expression were abolished by YYLLVR combined with ACE2 inhibitor (DX600) treatment. It had a protective effect against Ang II-induced apoptosis, restored the tube formation ability of endothelial cells, and improved their excessive migration and proliferation. With the addition of the ACE2 inhibitor, the expression of IL-1β increased (P < 0.05). The ACE2 activity was increased from 2.03 ± 0.22 to 3.27 ± 0.17 U/mg when treated with 100 μM YYLLVR in HUVECs (P < 0.05). Our study provides insights into the potential of YYLLVR as a novel ACE2-activating peptide with therapeutic potential for managing hypertension and endothelial dysfunction.