School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, People's Republic of China; Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, People's Republic of China; National Experimental Teaching Demonstration Center Food Engineering and Quality and Safety, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, People's Republic of China; Food (edible fungus) Processing Technology Research Center of Qing-Yuan, Hangzhou, Zhejiang 310018, People's Republic of China.
School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang 310018, People's Republic of China; Food (edible fungus) Processing Technology Research Center of Qing-Yuan, Hangzhou, Zhejiang 310018, People's Republic of China.
Int J Biol Macromol. 2024 Oct;278(Pt 4):134998. doi: 10.1016/j.ijbiomac.2024.134998. Epub 2024 Aug 22.
Grifola frondosa has garnered significant popularity as an edible mushroom attributable to its exceptional taste and nutritional benefits. This study isolated APPLRP, a potent ACE-inhibitory peptide, from the alcohol-soluble fraction of Grifola frondosa. The underlying mechanisms of APPLRP in antihypertension were explored through computational chemistry, cell experiments, and zebrafish model. Results demonstrated that APPLRP was an active competitive ACE inhibitor (IC = 29.93 μM) that could bind to the active pocket S2 and S1' of ACE. APPLRP exhibited resistance to pepsin and pancreatin digestion. In vitro experiments revealed that APPLRP significantly attenuated Ang II-induced VSMCs proliferation and migration by down-regulating AT1R expression and inhibiting ERK1/2 and STAT3 phosphorylation. APPLRP intervention significantly ameliorated myocardial fibrosis, as evidenced by reductions in cardiac output, blood flow velocity, and cardiac collagen deposition levels in Ang II-induced hypertensive zebrafish model. Furthermore, APPLRP improved vascular remodeling in hypertensive zebrafish, indicated by increased vessel diameter and decreased vessel wall thickness. Notably, APPLRP treatment resulted in down-regulation of ACE and up-regulation of ACE2 expression in the vessels of hypertensive zebrafish. These findings indicated that APPLRP was a representative component of Grifola frondosa peptides, and its antihypertensive effects were associated with ACE inhibition and the improvement of VSMCs-mediated vascular remodeling.
灰树花作为一种具有独特口感和营养价值的食用蘑菇而备受欢迎。本研究从灰树花的醇溶性部分中分离得到一种强效 ACE 抑制肽 APPLRP。通过计算化学、细胞实验和斑马鱼模型探索了 APPLRP 降压的潜在机制。结果表明，APPLRP 是一种有效的竞争性 ACE 抑制剂（IC=29.93μM），可与 ACE 的活性口袋 S2 和 S1'结合。APPLRP 对胃蛋白酶和胰蛋白酶消化具有抗性。体外实验表明，APPLRP 通过下调 AT1R 表达并抑制 ERK1/2 和 STAT3 磷酸化，显著抑制 Ang II 诱导的 VSMCs 增殖和迁移。APPLRP 干预显著改善了 Ang II 诱导的高血压斑马鱼模型中的心肌纤维化，表现为心输出量、血流速度和心脏胶原沉积水平降低。此外，APPLRP 改善了高血压斑马鱼的血管重塑，表现为血管直径增加和血管壁厚度降低。值得注意的是，APPLRP 治疗导致高血压斑马鱼血管中 ACE 的下调和 ACE2 的上调。这些发现表明，APPLRP 是灰树花肽的代表性成分，其降压作用与 ACE 抑制和改善 VSMCs 介导的血管重塑有关。
