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Hypertension is a major risk factor for cardiovascular diseases, leading to millions of deaths every year worldwide. Pharmacological interventions are the major therapy for hypertension treatment, including ACE inhibitors and AT1R blockers. However, side effects are often accompanied with the administration of synthetic drugs; many cases of hypertension are still not under control. Hence, there has been considerable interest over the past years in developing alternatives from natural sources for combating hypertension. One of the promising compounds are food-derived bioactive peptides. This study aimed to evaluate the modulatory effects of four spent hen muscle-derived peptides [VRP, LKY, VRY, and VVHPKESF (V–F)] on angiotensin II (Ang II)-induced inflammation in rat vascular smooth muscle A7r5 cells.
A7r5 cells were treated with 50 μM peptides for 1 h followed by 1 μM Ang II treatment for up to 24 h for the detection of iNOS and COX2. In some experiments, the antagonist of AT1R (losartan potassium; 50 μM), Ang II type 2 receptor (AT2R) (PD123319; 1 μM), or MasR (A779; 1 μM) was added with peptides. To study the involvement of the intracellular signaling pathway, A7r5 cells were treated with 50 μM peptides for 1 h before 1 μM Ang II treatment for 15 min for the detection of signaling pathways including nuclear factor kappa B (NF-kB) p65 and mitogen-activated protein kinases (MAPKs) members including p38, c-Jun N-terminal kinases (JNK), and extracellular signal-regulated kinases 1/2 (ERK1/2).
Only V–F could significantly attenuate Ang II-stimulated inflammation via the inhibition of NF-kB and p38 MAPK signaling, being dependent on the Mas receptor (MasR) not on the Ang II type 1 or type 2 receptor (AT1R or AT2R). V–F accelerated Ang II degradation by enhancing
cellular ACE2 activity, which was due to ACE2 upregulation other than a direct ACE2 activation. These findings demonstrated that V–F ameliorated Ang II-induced inflammation in A7r5 cells via the ACE2/Ang (1–7)/MasR axis. Three peptide metabolites of V–F−VHPKESF, PKESF, and SF−were identified but were not considered major contributors to V–F’s bioactivity. The regulation of peptide V–F on vascular inflammation supported its functional food or nutraceutical application in the prevention and treatment of hypertension and cardiovascular diseases.
In summary, among four chicken muscle-derived peptides (VRP, LKY, VRY, and V–F), only V–F significantly inhibited Ang II-induced inflammatory responses in A7r5 cells. The protective effect of V–F in ameliorating Ang II-stimulated vascular inflammation indicated its potential in regulating blood pressure in vivo, which awaits to be explored in animals in the near future. Prior to that, its gastrointestinal fate and transepithelial transport are warranted to be investigated soon.