br Improvement of endothelial function The vascular endothel

Improvement of endothelial function The vascular endothelium is a single layer of Adenine HCl that lines the inner surface of all blood vessels and the heart. In addition to function as a selective barrier to prevent the diffusion of macromolecules from the blood lumen to the intestinal space, the vascular endothelium is now considered as the biggest endocrine organ in the body (Münzel et al., 2008, Schulz et al., 2011). Endothelial cells secrete various vasoactive agents such as the vasodilating NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF) as well as the vasoconstricting endothelin I, Ang II and thromboxane (Vanhoutte, 1989). An imbalance in the relative contribution of endothelium-derived relaxing and contracting factors is a feature of endothelial dysfunction (Zhao, Chen, Yao, & Chen, 2005). Endothelial dysfunction has been shown in the elderly, in patients with hypertension, diabetes, hypercholesterolemia, and smoking (Münzel et al., 2008, Schulz et al., 2004), and is an early feature in the pathophysiology of metabolic syndrome and several cardiovascular disorders such as atherosclerosis, hypertension and heart failure (Fichtlscherer et al., 2004, Halcox et al., 2002). Improvement of endothelial function has been reported in studies of the blood pressure-lowering activity of ACEi peptides. The antihypertensive activity of ovotransferrin-derived IRW is due partially to its vasorelaxation activity. IRW exhibited relaxation in an isolated SHR mesenteric artery; pretreatment with N-nitro-l-arginine methyl ester (l-NAME), a endothelial nitric oxide synthase (eNOS) inhibitor, reduced IRW-mediated vasodilation, suggesting a key role of NO production (Majumder et al., 2013a). Indeed, eNOS expression was significantly enhanced in both the mesenteric artery and aorta, further supporting the role of NO in the vasorelaxation activity of IRW (Majumder et al., 2013a). The endothelium-dependent vasodilator activity of pentapeptide RADHP was also associated with enhanced NO formation as pretreatment with l-NAME inhibited vasodilation (Nakamura et al., 1995, Miguel et al., 2007). Milk casein hydrolysate containing tripeptides IPP and VPP was reported to improve the vascular endothelial function of subjects with stage I hypertension (Hirota et al., 2011). VPP and IPP were able to increase the mRNA expression of eNOS (Yamaguchi, Kawaguchi, & Yamamoto, 2009). Further study showed that both VPP and IPP induced endothelium-dependent relaxation in isolated aortic rings was related to enhanced production of vasodilating substances including NO (Hirota et al., 2011). Interestingly, vasorelaxation effect of IPP may be mediated through Mas receptor as the formation of Ang1-7 was enhanced (Ehlers, Nurmi, Turpeinen, Korpela, & Vapaatalo, 2011); in contrast to Ang II, Ang1-7 is vasodilating. Relaxation induced by α-lactorphin (YGLF) and β-lactorphin (YLLF), two opioid peptides derived from milk proteins α-lactalbumin and β-lactoglobulin, respectively, involved NO but not through EDHF or vasodilating prostanoids (Sipola et al., 2002, Yoshikawa et al., 1986). The relaxation induced by casoxin D (YVPFPPF), an anti-opioid peptide derived from human casein, was not affected by l-NAME but was antagonized by a cyclooxygenase inhibitor; its relaxation was mediated by bradykinin B1 receptor (Yoshikawa et al., 1994). Although NO might be involved in vasorelaxation, binding to neurokinin (NK1) receptors was thought to be the mechanism of action of casomokinin L (YPFPPL) (Fujita et al., 1996). IQW and LKP are other two identified ACEi peptides from ovotransferrin; although relaxation in both peptide-treated groups was significantly decreased by l-NAME pretreatment, expression of eNOS was not affected (Majumder et al., 2015b), suggesting the restoration of NO-mediated vasorelaxation may have been achieved with the peptides by increasing NO bioavailability.