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. 2019 May;63(9):e1900063.
doi: 10.1002/mnfr.201900063. Epub 2019 Apr 10.

Egg White-Derived Antihypertensive Peptide IRW (Ile-Arg-Trp) Reduces Blood Pressure in Spontaneously Hypertensive Rats via the ACE2/Ang (1-7)/Mas Receptor Axis

Affiliations

Egg White-Derived Antihypertensive Peptide IRW (Ile-Arg-Trp) Reduces Blood Pressure in Spontaneously Hypertensive Rats via the ACE2/Ang (1-7)/Mas Receptor Axis

Wang Liao et al. Mol Nutr Food Res. 2019 May.

Abstract

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.

Keywords: ACE2; bioactive peptides; blood pressure; hypertension.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
IRW decreases blood pressure of SHRs via the ACE2/Ang (1‐7)/MasR axis. A779 (48 µg per kg BW per h) or saline was infused 7 days prior to starting IRW treatment. The co‐treatment period of A779 and IRW was 7 days. A) Systolic pressure, B) diastolic pressure, C) mean arterial pressure, and D) heart rate were recorded over a 24‐h period. Data represented as mean ± SEM from six animals per treatment group. NS indicated no significant difference.
Figure 2
Figure 2
IRW modulates levels of circulating RAS components. Plasma from the rats were collected at the end point to evaluate the levels of circulating A) Ang II, B) ACE2, C) Ang (1‐7), D) ACE concentration, and E) ACE activity. Data represented as mean ± SEM from four to six animals per treatment group. *indicated p < 0.05, as compared with the untreated control.
Figure 3
Figure 3
IRW upregulates expressions of ACE2 and MasR in aorta of SHRs. Tissues were collected at the end point. Total proteins were extracted from aorta of SHR. Expressions of A) ACE2, B) MasR, C) ACE, D) AT1R, and E) AT2R were normalized to β‐actin. Data represented as mean ± SEM from four to six animals per treatment group.
Figure 4
Figure 4
Activation of ACE2/Ang (1‐7)/MasR axis by IRW contributes to improving endothelium‐dependent vasorelaxation. A) Ex vivo cumulative response curve to MCh in isolated mesenteric arteries were performed. Tissues were collected at the end point. Total proteins were extracted from aorta of SHR. Expressions of B) p‐Akt and C) p‐eNOS were normalized to the corresponding total forms. Data represented as mean ± SEM from four to six animals per treatment group.
Figure 5
Figure 5
Activation of ACE2/Ang (1‐7)/MasR axis by IRW contributes to attenuating vascular inflammation. Plasma from the rats were collected at the end point to evaluate the levels of circulating A) IL‐6 and B) MCP1. Tissues were collected at the end point. Total proteins were extracted from aorta. Expressions of C) IκBα and D) COX2 were normalized to GAPDH. Data represented as mean ± SEM from four to six animals per treatment group.
Figure 6
Figure 6
IRW treatment did not affect ERK1/2 MAPK or MMP9 expression in aorta of SHRs. Tissues were collected at the end point. Total proteins were extracted from the aorta of SHR. A) Expression of p‐ERK1/2 was normalized to total ERK1/2; B) expression of MMP9 was normalized to GAPDH. Data represented as mean ± SEM from four to six animals per treatment group.

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