Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells
Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells
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DOI：
10.1021/acs.jafc.2c04045
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发表时间：
2022-08-30
影响因子：
6.1
通讯作者：
Matsui，Toshiro
中科院分区：
文献类型：
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作者：
Gao，Guanzhen;Nakamura，Saya;Matsui，Toshiro
在这里，血管舒张剂Mas受体（MasR）表达上调橙皮苷在自发性高血压大鼠在人脐静脉内皮细胞（HUVECs）的机制进行了研究。用1 μ M橙皮苷培养HUVECs 2h，测定一氧化氮（NO）的产生和血管运动相关受体的表达。橙皮苷能显著促进HUVECs产生NO（224.1 ± 18.3%，P <0.01）。仅MasR表达上调（141.2 ± 12.5%，P <0.05vs对照），而MasR拮抗剂对橙皮苷诱导的NO产生无影响。当瞬时受体电位香草素1（TRPV1）被沉默RNA敲低或Ca2 +/钙调蛋白依赖性激酶II（CaMKII）和p38丝裂原活化蛋白激酶（p38 MAPK）被抑制时，由橙皮苷引起的MasR表达增加被废除。抑制CaMKII和内皮型NO合酶（eNOS）可抑制橙皮苷诱导的NO生成。构效关系分析表明，黄酮类化合物扭曲骨架上的B环3 ′位带有羟基，是影响TRPV 1活性的关键因素。综上所述，证明橙皮苷可以刺激TRPV 1介导的级联反应，导致两个信号传导轴的激活，即HUVEC中的CaMKII/p38 MAPK/MasR表达和CaMKII/eNOS/NO产生。
Here, the mechanism of vasorelaxant Mas receptor (MasR) expression elevated by hesperidin in spontaneously hypertensive rats was investigated in human umbilical vein endothelial cells (HUVECs). HUVECs were cultured with 1 μM hesperidin for 2 h, following the measurements of nitric oxide (NO) production and vasomotor-related receptors’ expression. Hesperidin significantly promoted NO production (224.1 ± 18.3%,P< 0.01 vs control) in the HUVECs. Only the MasR expression was upregulated (141.2 ± 12.5%,P< 0.05 vs control), whereas a MasR antagonist did not alter the hesperidin-induced NO production. When a transient receptor potential vanilloid 1 (TRPV1) was knocked down by silencing RNA or Ca2+/calmodulin-dependent kinase II (CaMKII) and p38 mitogen-activated protein kinase (p38 MAPK) were inhibited, the increased MasR expression by hesperidin was abrogated. The inhibitions of CaMKII and endothelial NO synthase (eNOS) abolished the hesperidin-induced NO production. The structure–activity relationship analysis of flavonoids demonstrated that the B ring of the twisted flavonoid skeleton with a hydroxy group at the 3′ position was a crucial factor for TRPV1 stimulation. Taken together, it was demonstrated that hesperidin may stimulate TRPV1-mediated cascades, leading to the activation of two signaling axes, CaMKII/p38 MAPK/MasR expression and CaMKII/eNOS/NO production in HUVECs.