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Hypertension is a risk factor for cardiovascular diseases, affecting about 25% of adults worldwide. Although the pathophysiology of essential hypertension is multifactorial and complicated, an over activated renin angiotensin system (RAS) is considered as a major factor, given the essential role of the RAS in regulating blood pressure. Given the side effects generated by prolonged use of antihypertensive drugs, food protein–derived antihypertensive peptides have attracted substantial interests as a safer alternative. 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.
Twelve to fourteen-week-old male Spontaneously Hypertensive Rats (SHRs, 290.0 ± 10 g) were given standard rat chow and water ad libitum. Thirteen to fifteen-week-old male SHRs were surgically implanted with telemetry transmitters for chronic blood pressure monitoring. The animals were randomly assigned into four groups: Untreated (n = 6), IRW (15 mg per kg body weight, n = 6), MasR antagonist A779 (48 µg per kg body weight per h, n = 6), and IRW+A779 (n = 6). Basal blood pressure (Day-7) was recorded, and then an osmotic pump loaded with A779 was implanted subcutaneously into the animal. An osmotic pump (ALZET) filled with saline was implanted into animals without A779 treatment. A779 was infused for 7 days prior to the start of IRW treatment. IRW was dissolved in 20 mL of Ensure and administered orally once per day for 7 days. Real-time blood pressure was monitored and blood samples were collected at the end point.
The mean artery pressure of SHR was reduced from 147.82 to 126.85 mmHg by 7-day IRW oral administration. Both systolic pressure and diastolic pressure were reduced during the treatment period IRW treatment resulted in increased circulating ACE2 and Ang (1-7) levels, but decreased the concentration of Ang II significantly, which implicated the potential of IRW in increasing circulating ACE2 to decrease blood pressure in SHRs.
IRW reduces blood pressure in SHRs via the ACE2/Ang (1-7)/MasR axis, demonstrating the role of IRW as an ACE2 activator in vivo; activation of ACE2 contributes to enhanced endothelium-dependent vasorelaxation and reduced vascular inflammation. Blood pressure-lowering activity of numerous ACE-inhibitory peptides is not due to the inhibition of ACE; the establishment of a role of the ACE2/Ang (1-7)/MasR axis in this study thus sheds new lights into the molecular targets of food protein–derived antihypertensive peptides. While, only male SHR was used in this study, it would be of interest to investigate if there is gender difference.