ACE inhibition is often thought to

ACE inhibition is often thought to play a central role in the mechanisms of blood pressure reduction in vivo, and most ACE inhibitory (ACEi) peptides were characterized based on in vitro ACE inhibition. A relationship between in vitro ACE inhibition and antihypertensive activity, however, is not apparent. For example, peptide KVLPVPN derived from β-casein showed significant blood pressure-lowering activity in vivo, despite its weak in vitro ACEi activity (FitzGerald et al., 2004), suggesting possible involvement of other mechanisms other than ACE inhibition. The pathophysiology of hypertension is complicated. Hypertension develops from a complex interaction of genetic, environmental and many other factors such as increased sympathetic nervous system activity, increased levels of long-term high sodium intake, inadequate dietary intake of potassium and calcium, elevated RAS activity, endothelial dysfunction, abnormalities in vessel resistance due to vascular inflammation, increased activity of vascular growth factors, and altered cellular ion channel (Foëx and Sear, 2004, Hall et al., 2012, Sarzani et al., 2008). The antihypertensive activity of YGLF (a peptide derived from bovine α-lactalbumin) is due to the stimulation of opioid receptors and nitric oxide (NO)-induced vasodilation function (Ijas et al., 2004). Moreover, milk lactoferrin-derived peptide RPYL was thought to function as an Ang II type 1 (AT1) receptor antagonist (Fernandez-Musoles et al., 2013); Ang II acts mainly through AT1 receptor causing vasoconstriction and hypertension. Antihypertensive activity of egg-derived peptide IRW also appears to be mediated through increased NO-mediated vasodilation, reduced vascular inflammation, and up-regulated neuronal nitric oxide synthase of ACE2 (Majumder et al., 2013a, Majumder et al., 2015a). ACEi peptides have also been shown to exhibit antihypertensive effects through mechanisms other than the classical circulatory RAS system. The objectives of this review are to discuss the newly emerging mechanisms of ACEi peptides and further considerations to enhance efforts towards the translation of antihypertensive peptides into functional food ingredients.
Up-regulation of ACE2 Within the RAS, ACE is the key enzyme responsible for conversion of Ang I, an inactive decapeptide, into Ang II, a vasoconstrictive octapeptide (Zhuo, Ferrao, Zheng, & Li, 2013). Ang II mediates its biological function through binding with two G-protein-coupled receptors: AT1 and Ang II type 2 (AT2) receptors. As shown in Fig. 1, these receptors differ in their biological functions: AT1 receptor is associated with vasoconstriction, inflammation, growth and fibrosis, while AT2 receptor is associated with apoptosis and vasodilation. AT1 receptor shares partial homology with AT2 receptor in amino acid constitution and it is the dominant subtype after birth. Therefore, inhibition of ACE (reducing Ang II generation) and blocking AT1 receptor (as receptor antagonists) are the widely used strategies for controlling blood pressure (Contreras et al., 2003, Donnelly, 1992). An alternate arm of the RAS, ACE2 is also involved in counterbalancing the harmful effects of Ang II (Fig. 1). First identified as a homologue of ACE (Donoghue et al., 2000), ACE2 cleaves the carboxyl-terminal phenylalanine of Ang II to form Ang (1–7), which can exert inhibitory effect on Ang II-induced vasoconstriction via binding to the Mas receptor (Santos et al., 2003, Vickers et al., 2002). Alternatively, ACE2 hydrolyzes Ang I to form Ang (1–9), which can be further converted by ACE to Ang (1–7). Nevertheless, the ACE2-Ang (1–7)-Mas pathway is more efficient in reducing the Ang II-induced effect than the ACE2-Ang (1–9) pathway (Vickers et al., 2002). In spontaneously hypertensive rats (SHRs), increased ACE2 expression contributes to reduced blood pressure, attenuated perivascular fibrosis, decreased oxidative stress and inhibited cardiac remodeling (Díez-Freire et al., 2006, Keidar et al., 2007, Lo et al., 2013, Zhong et al., 2004). ACE2 knockout (ACE2KO) mice showed enhanced Ang II-induced fibrosis, superoxide production, inflammatory cytokine level and hypertrophic cardiomyopathy (Alghamri et al., 2013). Supplementation of human recombinant ACE2 (hrACE2) was found to blunt Ang II-mediated hypertrophic response and superoxide production in ACE2 knockout (ACE2KO) mice (Zhong et al., 2010), which further confirmed the significant roles of ACE2 in cardiovascular functions. Therefore, activation of ACE2 represents a potential target for blood pressure control (Kulemina and Ostrov, 2011, Prada et al., 2008). Interestingly, several established antihypertensive ACEi drugs such as enalapril and telmisartan also show concomitant upregulation of ACE2 expression (Yang et al., 2013, Zhong et al., 2011). Our transcriptomics study showed that mRNA expression of ACE2 in mesenteric artery of SHRs was significantly increased by oral administration of tripeptide IRW, which sheds light on the new mechanism of the ACEi peptide in vivo (Majumder et al., 2015a). Our recent research also showed that ACE2 expression in the aorta was enhanced by the peptide treatment (unpublished data). IRW is the first ACEi peptide reported to show ACE2 activation property; our ongoing research will determine if up-regulation/activation of ACE2 is a common feature of ACEi peptides.