Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells

Abstract

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.

Recent understanding of the mechanisms of the biological activities of hesperidin and hesperetin and their therapeutic effects on diseases

“… [ 160 ] Cardiac hypertrophy Hsd Isoproterenol-induced rats Interfering with NF‐κB signaling via JNK phosphorylation [ 161 ] Hypertensive Hsd Spontaneously hypertensive rats Improving NO bioavailability in endothelial cells. [ 162 ] Hypertensive Hsd Human umbilical vein endothelial cells Spontaneously hypertensive rats Stimulate CaMKII/p38 MAPK/MasR expression and CaMKII/eNOS/NO production [ 163 ] Parkinson's Disease Hsd 6-OHDA-induced mice Attenuate the striatal levels of proinflammatory cytokines tumor necrosis factor-α, interferongamma, interleukin-1β, interleukin-2, interleukin-6 [ 164 ] NeuroinflammationMemory Impairments Hst LPS-induced HT-22 cells BV2 cells LPS-induced mice Through the NF-κβ signaling pathway reduced the protein expression level of TNF-α and IL-1β cytokines [ 165 ] Ischemic stroke Hst Middle cerebral artery occlusion mice Inhibit the TLR4-NF-κβ pathway [ 166 ] Temporal lobe epilepsy Hst Kainic acid-induced mice Inhibit the expression of pro-inflammatory molecules [ 167 ] Parkinson's Disease Hsd OHDA-induced zebrafish Downregulated the kinases lrrk2 and gsk3β along with casp3, casp9, polg …”

Research Progress of Flavonoids Regulating Endothelial Function

“…Naringenin attenuates high-glucose-induced apoptosis in HUVECs, which may play a role in increasing HO-1 expression in HUVECs through up-regulation of PI3K/Akt or JNK pathways [ 75 ]. The vasodilatory effect of naringenin mainly involves the inhibition of multiple Ca2+ channels, whereas hesperidin stimulates a transient receptor potential vanilloid 1 (TRPV1)-mediated cascade reaction that activates the expression of both the CaMKII/p38 MAPK/MasR and the CaMKII/eNOS/NO signaling axes in HUVEC to promote NO production and vasorelaxant Mas receptor (MasR) expression [ 76 , 77 ]. Multiple nanodelivery systems increase the oral availability and targeting of compounds.…”