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. 2010 Aug 1;49(3):339-47.
doi: 10.1016/j.freeradbiomed.2010.04.022. Epub 2010 Apr 25.

Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels

Nicholas K H Khoo  1 , C Roger White, Lucas Pozzo-Miller, Fen Zhou, Chad Constance, Takafumi Inoue, Rakesh P Patel, Dale A Parks
Affiliations

Dietary flavonoid quercetin stimulates vasorelaxation in aortic vessels

Nicholas K H Khoo et al. Free Radic Biol Med. .

Abstract

Considerable epidemiological evidence indicates that dietary consumption of moderate levels of polyphenols decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but can involve changes in rates of nitric oxide (NO) generation by endothelial nitric oxide synthase (eNOS). We examined the vascular responses to quercetin using a combination of biochemical and vessel function criteria. Quercetin treatment for 30min enhanced relaxation of rat aortic ring segments. Moreover, the addition of L-NAME (100muM) or charybdotoxin (ChTx) blocked quercetin-mediated vasorelaxation thus demonstrating the effect was partially dependent on NOS and endothelium-derived hyperpolarizing factor (EDHF). Additionally, bovine aortic endothelial cells (BAEC) treated with quercetin showed a rapid increase of intracellular Ca(2+) concentrations as well as a dose- and time-dependent stimulation of eNOS phosphorylation with a concomitant increase in NO production. These results demonstrate that quercetin-mediated stimulation of eNOS phosphorylation increases NO bioavailability in endothelial cells and can thus play a role in the vascular protective effects associated with improved endothelial cell function.

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Figures

Figure 1
Figure 1. Quercetin attenuates phenylephrine (PE)-induced contraction in rat aortic vessels
Line graphs represent concentration-response curves of aortic ring segments to PE. (A) Contractile response of rat aortic ring segments incubated with vehicle control (DMSO), 5 and 10 μM quercetin for 30 min. (B) Aortic rings were incubated with 100 μM L-NAME for 15 minutes followed by DMSO or quercetin treatment for 30 minutes. Aortic ring segments were incubated with DMSO or 5 μM quercetin for 30 min followed by an Ach dose response (3×10−9–3×10−5 M). Results are presented as mean ± SEM, n=8–14. #, p<0.05, significant difference compared to control; *, p<0.05, significant difference compared to all groups (control, L-NAME, and L-NAME and quercetin).
Figure 2
Figure 2. Quercetin stimulates eNOS phosphorylation at Ser1179, NO production, and cGMP
Confluent BAECs were treated with 5 or 10 μM quercetin for 30 and 60 min. (A) Top panel is a representative Western blot; bottom panel is the densitometric intensity determined digitally. (B) Quercetin treatment stimulated NO release from BAECs. NO generation was determined in quercetin-treated confluent BAECs for the indicated times using Sievers nitric oxide analyzer (NOA). The levels of nitrite have been normalized to protein concentration (basal NO2− = 1.04 ± 0.09 nmoles/mg protein) and are reported as a percent of the vehicle control (DMSO) at each individual time point (30, 60, and 120 min). A23187 was used as a positive control. (C) Rat aortic ring segments were incubated with or without 25 μM BAPTA/AM for 30 min followed by the treatment of 5 μM quercetin for 60 min. The aortic ring segments were immediately snap frozen in liquid nitrogen and cGMP values were determined using the cGMP enzyme immunoassay assay from Cayman. Diethylenetriamine/NO (DETA/NO represented as D), a nitric oxide donor, was used as a positive control. Results were derived from at least four independent experiments and data were expressed as mean ± SEM. *, p<0.05 vs control; &, p<0.05 vs all groups.
Figure 3
Figure 3. Quercetin increases intracellular Ca2+ pools in BAECs while BAPTA/AM blocks quercetin-induced eNOS phosphorylation at Ser1179
(A) BAECs were loaded with the fluorescent probe fura2/AM (5 μM) for 15 minutes, rinsed with HBSS, placed in a recording chamber mounted on a fixed-stage upright microscope, equilibrated and then treated with 2.5 μM quercetin (left panel) or DMSO (right panel). A representative recording from a single coverslip showing Ca2+ traces from individual cells following the treatment of quercetin. Each run had 10–20 cells per experiment. The arrows indicate when quercetin and DMSO were added. Results were derived from at least seven independent experiments. (B) BAECs were pretreated with 25 μM BAPTA/AM for 30 min followed by a 5 μM quercetin treatment for 30 min. Top panel is a representative Western blot of eNOS phosphorylation at Ser1179 and eNOS was used as a loading control; bottom panel is the densitometric intensity determined digitally. Data is represented as the mean ± SEM, n=4–6. *, p<0.05 vs control
Figure 4
Figure 4. Overexpression of catalase inhibits quercetin-stimulated eNOS phosphorylation at Ser1179
(A) Catalase transduction using 12.5, 25, 50 MOI Ad.Cat significantly increased catalase activity in BAECs compared to Ad.Empty transduced controls. (B) Catalase transduced BAECs were treated with DMSO or quercetin for 30 min. Top panel is a representative Western blot of eNOS phosphorylation at Ser1179 and eNOS was used as a loading control; bottom panel is the densitometric intensity determined digitally. Results are expressed as mean ± SEM, n=6. Ø, no treatment; 25E, 25 MOI Ad.Empty; 50E, 50 MOI Ad.Empty. *P<0.05, significant difference compared to all groups (non-transduced controls, 25 and 50 Ad.Empty transduced BAECs); *, p<0.05 vs Ad.Empty transduced BAECs treated only with DMSO; %, p<0.05- quercetin vs DMSO for respective adenovirus control (i.e.- BAECs transduced with 50 MOI Ad.Empty treated with quercetin compared to DMSO).
Figure 5
Figure 5. Quercetin treatment induces EDHF
Rat aortic ring segments were equilibrated (basal) and then contracted with 70 mM KCl. The rings were rinsed and allowed to re-equilibrate back to baseline and then treated with or without 50 nM charybdotoxin (ChTx) for 30 min. Immediately after, the rings were contracted with another dose of 70 mM KCl (maximal contraction) followed by 5 μM quercetin treatment for 30 min in intact (A) and denuded vessels (B). At the end of the experiments, acetylcholine (Ach) dose responses were performed to ensure maximal relaxation. Results are presented as mean ± SEM, n=8–14. *, p<0.05, significant difference compared to all groups.
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