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Global Translational Medicine Impact of flavonoids on vascular health

site Ser1177 and dephosphorylation at the inhibition site Flavonoids’ potent-free radical scavenging activity
Thr495. The latter mechanism involves a prooxidant safeguards NO from ROS-mediated inactivation,
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effect, as indicated by its prevention with permeant analogs preventing peroxynitrite and nitrotyrosine formation
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20
of SOD. However, the impact of isolated flavonols such and contributing to their in vivo benefits. In addition,
as quercetin on eNOS expression and endothelial NO they impede LDL oxidation, a key step in atherosclerotic
production in in vitro studies remains contentious, with plaque formation. Their chelation of pro-oxidant metals
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conflicting results based on oxidative stress conditions. further mitigates Fenton reactions and the generation
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Quercetin may scavenge NO under no oxidative stress, of highly DNA-damaging hydroxyl radicals. Beyond
leading to its auto-oxidation and generation of O , ROS scavenging, flavonoids enhance NO availability by
2-
ultimately inactivating NO. It could also reduce eNOS inhibiting ROS-generating enzymes like 5-lipoxygenase,
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expression in tumor necrosis factor-alpha (TNF-α)- COX, xanthine oxidase, and NADPH oxidase, while
stimulated endothelial cells and normalize upregulated upregulating antioxidant enzymes such as SOD,
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eNOS in aortas from spontaneously hypertensive CAT, and peroxidase. Moreover, they may prevent
rats (SHR). In aortic rings from normotensive and tetrahydrobiopterin oxidation and eNOS uncoupling,
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hypertensive animals, quercetin therapy over an extended preserving eNOS function as an NO producer. Recent
period of time may not increase endothelium-dependent evidence suggests that flavonoids can improve endothelial
relaxation to insulin, indicating a direct inhibitory function under hypertensive and hyperglycemic conditions
effect on PI3-K/Akt-dependent eNOS phosphorylation. by attenuating ER stress through ROS reduction, likely due
However, due to its antioxidant qualities, quercetin may to their antioxidant properties. However, further research
improve impaired endothelium-dependent vasodilation is needed to solidify the protective effects against ER stress-
under conditions of increased oxidative stress, suggesting associated oxidative stress and vascular dysfunction. 36,56
that NO production is not directly affected but rather that Flavonoids further contribute to endothelial protection
NO-dependent vasodilation is increased due to reduced by downregulating vasoconstrictor mediators, including
O -driven NO inactivation. 33,65 Ang II, ET-1, and PGIs. Their interference with Ang
2
Moreover, flavonoids possess the ability to increase II synthesis involves modulating ACE activity or its
the production of NO in endothelial cells by suppressing signaling pathways. 26,46 Quercetin and epicatechin, among
the expression of caveolin-1 (Cav-1). Cav-1 functions others, suppress ET-1 production through Akt-mediated
as a significant negative regulator of eNOS activity in transcriptional regulation, demonstrated in both in vitro
endothelial cells. This effect occurs through the activation and in vivo studies. 27,55
of extracellular-signal-regulated kinases 1/2 (ERK1/2) Molecular targets implicated in the vasculoprotective
and the inhibition of p38 mitogen-activated protein effects of flavonoids include arginase-2 (ARG2), nuclear
kinase (p38MAPK) signaling pathways. 66,67 In addition, factor erythroid 2-related factor 2 (Nrf2), and sirtuin
flavonoids have been shown to inhibit various isoforms 1 (SIRT-1). By reducing arginase-2 activity, flavonoids
of phosphodiesterases, which play a critical role in prevent L-arginine competition with eNOS, subsequently
NO-mediated relaxation and endothelium-dependent inhibiting NO formation. Activation of Nrf2 by quercetin
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relaxation. It is worth noting that certain flavonoids, such and EGCG upregulates antioxidant enzymes via the Nrf2/
as kaempferol, can enhance the relaxant response to the ARE pathway, enhancing cellular defense against oxidative
soluble guanylyl cyclase activator sodium nitroprusside. 69 stress. SIRT-1 directly interacts with eNOS, deacetylating
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Flavonoid-mediated inhibition of endothelium-derived it at Lys496 and Lys506 to promote vasodilation and
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vasoconstrictors, particularly PGIs, has been proposed as enhance eNOS activity. Given that downregulation or
a mechanism for preventing endothelial dysfunction, as pharmacological inhibition of SIRT-1 is closely linked
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evidenced by quercetin’s action. Conversely, flavonoids to endothelial dysfunction, recent evidence suggests
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can indirectly induce vasodilation by enhancing NO that quercetin may act as a SIRT-1 activator, potentially
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bioavailability through several pathways, which include ameliorating impaired endothelial function.
scavenging ROS, reducing endogenous eNOS inhibitors The vasculature harbors inherent anti-inflammatory
such as asymmetric dimethylarginine, blocking and anti-proliferative properties that augment the
vasoconstrictor release (endothelin-1 [ET-1] and potential antihypertensive and antiatherosclerotic effects
angiotensin II [Ang II]), and inhibiting enzymes involved of flavonoids. In the context of vascular pathology,
in NO inactivation (nicotinamide adenine dinucleotide inflammation stands as a pivotal element, characterized by
phosphate [NADPH] oxidase, acetylcholinesterase, and the excessive production of proinflammatory agents and
angiotensin-converting enzyme [ACE]). 71 adhesion molecules, frequently orchestrated by nuclear

Volume 3 Issue 2 (2024) 5 doi: 10.36922/gtm.2458