TY - JOUR
T1 - Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling
T2 - Evidence for a surface receptor
AU - Moreno-Ulloa, Aldo
AU - Romero-Perez, Diego
AU - Villarreal, Francisco
AU - Ceballos, Guillermo
AU - Ramirez-Sanchez, Israel
N1 - Funding Information:
The work was partially funded by Cardero Therapeutics, Inc., NIH HL43617, DK92154, AT004277 and NIH/NIMHD-sponsored (P60 MD000220) to F. Villarreal. Aldo Moreno Ulloa (Ph.D. fellowship #388585), I. Ramirez-Sanchez, (post-doctoral fellowship #93759) and G. Ceballos (sabbatical fellowship #129889) from CONACYT, Mexico.
PY - 2014/6/15
Y1 - 2014/6/15
N2 - The consumption of cacao-derived products, particularly in the form of dark chocolate is known to provide beneficial cardiovascular effects in normal individuals and in those with vascular dysfunction (reduced nitric oxide [NO] bioavailability and/or synthesis). Upstream mechanisms by which flavonoids exert these effects are poorly understood and may involve the participation of cell membrane receptors. We previously demonstrated that the flavanol (-)-epicatechin (EPI) stimulates NO production via Ca+2-independent eNOS activation/phosphorylation. We wished to investigate the plausible participation of a cell surface receptor using a novel cell-membrane impermeable EPI-Dextran conjugate (EPI-Dx). Under Ca2+-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10 min with EPI or EPI-Dx at equimolar concentrations (100 nM). Results demonstrate that both EPI and EPI-Dx induced the phosphorylation/activation of PI3K, PDK-1, AKT and eNOS. Interestingly, EPI-Dx effects were significantly higher in magnitude than those of EPI alone. The capacity of EPI-Dx to stimulate cell responses supports the existence of an EPI cell membrane receptor mediating eNOS activation.
AB - The consumption of cacao-derived products, particularly in the form of dark chocolate is known to provide beneficial cardiovascular effects in normal individuals and in those with vascular dysfunction (reduced nitric oxide [NO] bioavailability and/or synthesis). Upstream mechanisms by which flavonoids exert these effects are poorly understood and may involve the participation of cell membrane receptors. We previously demonstrated that the flavanol (-)-epicatechin (EPI) stimulates NO production via Ca+2-independent eNOS activation/phosphorylation. We wished to investigate the plausible participation of a cell surface receptor using a novel cell-membrane impermeable EPI-Dextran conjugate (EPI-Dx). Under Ca2+-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10 min with EPI or EPI-Dx at equimolar concentrations (100 nM). Results demonstrate that both EPI and EPI-Dx induced the phosphorylation/activation of PI3K, PDK-1, AKT and eNOS. Interestingly, EPI-Dx effects were significantly higher in magnitude than those of EPI alone. The capacity of EPI-Dx to stimulate cell responses supports the existence of an EPI cell membrane receptor mediating eNOS activation.
KW - Endothelial cells
KW - Epicatechin
KW - PI3K/AKT
KW - eNOS
UR - http://www.scopus.com/inward/record.url?scp=84900793436&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2014.04.038
DO - 10.1016/j.bmcl.2014.04.038
M3 - Artículo
C2 - 24794111
SN - 0960-894X
VL - 24
SP - 2749
EP - 2752
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 12
ER -