Abstract
Polyphenols consumption has been associated with a lower risk of cardiovascular diseases (CVDs) notably through nitric oxide (NO)- and estrogen receptor α (ERα)-dependent pathways. Among polyphenolic compounds, chalcones have been suggested to prevent endothelial dysfunction and hypertension. However, the involvement of both the NO and the ERα pathways for the beneficial vascular effects of chalcones has never been demonstrated. In this study, we aimed to identify chalcones with high vasorelaxation potential and to characterize the signaling pathways in relation to ERα signaling and NO involvement. The evaluation of vasorelaxation potential was performed by myography on wild-type (WT) and ERα knock-out (ERα-KO) mice aorta in the presence or in absence of the eNOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). Among the set of chalcones that were synthesized, four (3, 8, 13 and 15) exhibited a strong vasorelaxant effect (more than 80% vasorelaxation) while five compounds (6, 10, 11, 16, 17) have shown a 60% relief of the pre-contraction and four compounds (12, 14, 18, 20) led to a lower vasorelaxation. We were able to demonstrate that the vasorelaxant effect of two highly active chalcones was either ERα-dependent and NO-independent or ERα-independent and NO-dependent. Thus some structure-activity relationships (SAR) were discussed for an optimized vasorelaxant effect.
Highlights
According to the World Health Organization (WHO), cardiovascular diseases are the first leading cause of death worldwide [1]
Synthetic polyhydroxylated chalcones 3, 6, 8 and 10 were synthesized through a two-step procedure starting from the corresponding methoxymethyl (MOM)-protected acetophenones and benzaldehydes
This strategy required an extra deprotection step compared to Claisen-Schmidt condensation of phenolic starting materials, it has led to a better overall yield as observed for the synthesis of chalcone 8 compared to literature data [20,21]
Summary
According to the World Health Organization (WHO), cardiovascular diseases are the first leading cause of death worldwide [1]. Epidemiological studies indicate that the prevalence of CVDs is lower in premenopausal women compared to age-matched men and significantly increases in women after menopause, suggesting a protective role of estrogens in premenopausal women [4,5] Both estrogen receptor α (ERα) and estrogen receptor β (ERβ) are involved in cardiovascular protection with a predominant role of ERα at the vascular level [6,7]. ERα, expressed by endothelial cells and co-localized with endothelial NO synthase (eNOS), has been identified as an eNOS activator through an Src/ERK1/2-dependent pathway both in human primary endothelial cells and mice [8,9] These endothelial effects are strengthened by clinical data reporting that menopausal hormone replacement therapy (MHT) prevents cardiovascular outcomes in perimenopausal women, confirming the role of estrogen receptor activation for the prevention of the endothelial dysfunction in women [10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
