H-Val-Pro-Pro-OH is a milk-derived tripeptide that inhibits Angiotensin I converting enzyme (ACE), with an IC50 of 9μM[1]. H-Val-Pro-Pro-OH can stimulate insulin signaling, especially phosphorylation of protein kinase B and insulin receptor (IR), to ameliorate insulin resistant[2]. H-Val-Pro-Pro-OH has been widely used in different animal models to regulate immune function and inhibit inflammatory responses[3].
In vitro, H-Val-Pro-Pro-OH pretreatment (50μM) for 12 hours can significantly inhibit the proliferation of vascular smooth muscle cells (VSMCs) induced by angiotensin II (Ang II)[4]. Treatment with 600μM H-Val-Pro-Pro-OH for 18 hours significantly enhanced glucose consumption in HepG2 cells, regulated the activity of glucose metabolism enzymes, and increased the protein levels of phosphorylated AKT (p-AKT) and GLUT2 in HepG2 cells[5]. Treatment with H-Val-Pro-Pro-OH (50μM) for 72 hours significantly increased lipid accumulation in 3T3-F442A cells, leading to a significant increase in PPARγ and adiponectin expression[6].
In vivo, H-Val-Pro-Pro-OH treatment via oral administration at a dose of 30mg/kg/day for 8 weeks alleviated the left ventricular hypertrophy, abnormal glomerular morphology and thickening of small arteries in the kidneys caused by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) in rats[7]. Oral administration of 125.4μmol/kg/day of H-Val-Pro-Pro-OH daily for 31 consecutive weeks delayed the development of atherosclerosis in male apoE(-/-) mice and reduced the expression of inflammatory factors[8].
References:
[1] Nakamura Y, Yamamoto N, Sakai K, et al. Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk[J]. Journal of dairy science, 1995, 78(4): 777-783.
[2] Li S, Bu T, Zheng J, et al. Preparation, bioavailability, and mechanism of emerging activities of Ile‐Pro‐Pro and Val‐Pro‐Pro[J]. Comprehensive Reviews in Food Science and Food Safety, 2019, 18(4): 1097-1110.
[3] Pérez-Vielma N M, Gómez-López M, Maldonado J, et al. Recognition of the interaction between the bioactive peptide Val–Pro–Pro and the minimal promoter region of genes SOD and CAT using QCM-D and docking studies[J]. Analytical Methods, 2023, 15(24): 2979-2988.
[4] Song T, Lv M, Sun B, et al. Tripeptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) regulate the proliferation and migration of vascular Smooth muscle cells by interfering Ang II-induced human umbilical vein endothelial cells derived EVs delivering RNAs to VSMCs in the co-culture model[J]. Journal of agricultural and food chemistry, 2020, 68(24): 6628-6637.
[5] Wang C, Zheng L, Zhao M. Molecular targets and mechanisms of casein-derived tripeptides Ile-Pro-Pro and Val-Pro-Pro on hepatic glucose metabolism[J]. Journal of Agricultural and Food Chemistry, 2023, 71(48): 18802-18814.
[6] Chakrabarti S, Wu J. Milk-derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) promote adipocyte differentiation and inhibit inflammation in 3T3-F442A cells[J]. PloS one, 2015, 10(2): e0117492.
[7] Nonaka A, Nakamura T, Hirota T, et al. The milk-derived peptides Val-Pro-Pro and Ile-Pro-Pro attenuate arterial dysfunction in L-NAME-treated rats[J]. Hypertension Research, 2014, 37(8): 703-707.
[8] Nakamura T, Hirota T, Mizushima K, et al. Milk-derived peptides, Val-Pro-Pro and Ile-Pro-Pro, attenuate atherosclerosis development in apolipoprotein E–deficient mice: a preliminary study[J]. Journal of medicinal food, 2013, 16(5): 396-403.
H-Val-Pro-Pro-OH是一种乳源活性三肽，可抑制血管紧张素转换酶(ACE)活性，IC50值为9μM[1]。H-Val-Pro-Pro-OH通过刺激胰岛素信号通路，增强蛋白激酶B磷酸化及胰岛素受体活化，从而改善胰岛素抵抗[2]，H-Val-Pro-Pro-OH已广泛应用于不同动物模型中调节免疫功能及抑制炎症反应[3]。
在体外，使用50μM的H-Val-Pro-Pro-OH预处理血管平滑肌细胞(VSMCs)12小时，能显著抑制血管紧张素II(Ang II)诱导的细胞增殖[4]。用600μM的H-Val-Pro-Pro-OH处理HepG2细胞18小时，可显著增强葡萄糖消耗量，调节糖代谢酶活性，并提高磷酸化AKT和GLUT2蛋白水平[5]。以50μM的H-Val-Pro-Pro-OH处理3T3-F442A细胞72小时，能显著促进脂质积累，同时增加PPARγ和脂联素表达[6]。
在体内，每日口服30mg/kg/day剂量的H-Val-Pro-Pro-OH连续8周，可缓解N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME)诱导的大鼠左心室肥厚、肾小球形态异常及肾小动脉增厚[7]。连续31周每日口服125.4μmol/kg剂量的H-Val-Pro-Pro-OH，能延缓雄性apoE(-/-)小鼠的动脉粥样硬化进展，并降低炎症因子表达水平[8]。