Chemical structures of 4-oxo-flavonoids in relation to inhibition of oxidized low-density lipoprotein (LDL)-induced vascular endothelial dysfunction.
Vascular endothelial dysfunction induced by oxidative stress has been demonstrated to be the initiation step of atherosclerosis (AS), and flavonoids may play an important role in AS prevention and therapy. Twenty-three flavonoids categorized into flavones, flavonols, isoflavones, and flavanones, all with 4-oxo-pyronenucleus, were examined for what structural characteristics are required for the inhibitory effects on endothelial dysfunction induced by oxidized low-density lipoprotein (oxLDL). Human vascular endothelial cells EA.hy926 were pretreated with different 4-oxo-flavonoids for 2 hs, and then exposed to oxLDL for another 24 hs. Cell viability and the level of malondialdehyde (MDA), nitric oxide (NO) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured, respectively. Then, correlation analysis and paired comparison were used to analyze the structure-activity relationships. Significant correlations were observed between the number of -OH moieties in total or in B-ring and the inhibitory effectson endothelial dysfunction. Furthermore, 3',4'-ortho-dihydroxyl on B-ring, 3-hydroxyl on C-ring and 2,3-double bondwere correlated closely to the inhibitory effects of flavonolson cell viability decrease and lipid peroxidation. 5,7-meta-dihydroxyl group on A-ring was crucial for the anti-inflammatory effects of flavones and isoflavones in endothelial cells. Moreover, the substituted position of B-ring on C3 rather than C2 was important for NO release. Additionally, hydroxylation at C6 position significantly attenuated the inhibitory effects of 4-oxo-flavonoids on endothelial dysfunction. Our findings indicated that the effective agents in inhibiting endothelial dysfunction include myricetin, quercetin, luteolin, apigenin, genistein and daidzein. Our work might provide some evidence for AS prevention and a strategy for the design of novel AS preventive agents.
Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing 400038, China; E-Mails:  longgyin8341@hotmail.com  (L.Y.);  jinxin41@hotmail.com  (X.J.);  xiguameimei-ye@163.com  (C.-Y.C.);  fuyujie2011@hotmail.com  (Y.-J.F.);  zhangting20091@hotmail.com  (T.Z.);  changhui1998@hotmail.com  (H.C.);  zhouyong19621@hotmail.com  (Y.Z.);  zhangqianyong2011@hotmail.com  (Q.-Y.Z).
Long
L
Yi
Xin
X
Jin
Chun-Ye
CY
Chen
Yu-Jie
YJ
Fu
Ting
T
Zhang
Hui
H
Chang
Yong
Y
Zhou
Jun-Dong
JD
Zhu
Qian-Yong
QY
Zhang
Man-Tian
MT
Mi
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000633:toxicity*; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein