Diets rich in citrus and citrus-based products have been negatively correlated with the risk of
cardiovascular disease, but so far no studies have been conducted to determine whether
naringenin and
hesperetin, two major
flavanones in citrus plants, influence endothelium
nitric oxide (NO) production. The aim of this study is to clarify estrogenic activities of
naringenin and
hesperetin and to examine whether they affect endothelial NO production via
estrogen receptor (ER) activation. Both
naringenin and
hesperetin were observed to promote growth of MCF-7 cells under greatly reduced
estrogen conditions and to suppress
estrogen-induced response.
Naringenin activated both
ERalpha and
ERbeta, whereas
hesperetin exhibited stronger potential to activate
ERalpha rather than
ERbeta.
Hesperetin, but not
naringenin, increased NO releases from human umbilical vein endothelial cells in a dose-dependent manner.
Hesperetin-induce responses were suppressed by ICI 182 780 and
actinomycin D. Real-time reverse transcription polymerase chain reaction (RT-PCR) and western-blotting analysis revealed that
hesperetin up-regulated endothelium
nitric oxide synthase (eNOS) expression. These results suggested that
hesperetin exerts an antiatherogenic effect, in part, via ER-mediated eNOS expression and subsequent increase of endothelial NO production. Distinct effects of
naringenin and
hesperetin on NO production also imply that
ERalpha might play the major role in
estrogen-induced eNOS expression. However, the inefficacy of
naringenin on NO production remains to be elaborately studied. Our findings add more proof to the molecular explanations for the health benefits of citrus used to prevent
cardiovascular disease, especially for postmenopausal women.