title: Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: role of MAPK- and JAK/STAT-signaling.
abstract: Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized LDL promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. This study investigated multiple mitogen-activated protein kinase (MAPK)-responsive death/survival signaling pathways, through which flavonoids of (-)epigallocatechin gallate (EGCG) and hesperetin exerted antiapoptosis in endothelial cells exposed to oxidized LDL. EGCG and hesperetin substantially diminished the oxidized LDL-induced 2',7'-dichlorofluorecein staining, suggesting that these flavonoids inhibited intracellular accumulation of oxidized LDL-triggered reactive oxygen species and consequent apoptosis. The Western-blot data revealed that oxidized LDL upregulated c-Jun N-terminal kinase (JNK) phosphorylation, which was rapidly reversed by EGCG and hesperetin. They mitigated the consequent activation of the JNK downstream on p53 and c-Jun. Moreover, oxidized LDL increased luciferase activity of p53 in endothelial cells transfected with a p53 promoter construct, the increase of which was strikingly downregulated by EGCG and hesperetin. Surprisingly, hesperetin but not EGCG attenuated phosphorylation of p38MAPK and its downstream c-myc and signal transducers and activators of transcription (STAT)1 evoked by oxidized LDL. This study also attempted to explore a linkage of Janus kinase (JAK)2/STAT3 activation to MAPK signaling in oxidized LDL-induced endothelial apoptosis. Notably, we found that the JAK2 inhibitor substantially blocked the JNK activation. Our findings suggest that EGCG and hesperetin may act as antiatherogenic agents blocking oxidized LDL-induced endothelial apoptosis via differential cellular apoptotic machinery. These data provide evidence that the interplay between p38MAPK and JAK-STAT pathways is involved in dietary flavonoid protection against oxidized LDL through hampering MAPK-dependent pathways involving the activation of JAK2.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Jung-Suk
authors.initials: JS
authors.lastname: Choi
authors.forename: Yean-Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Sung-Yong
authors.initials: SY
authors.lastname: Shin
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Bae
authors.forename: Dong Shoo
authors.initials: DS
authors.lastname: Kim
authors.forename: Geun-Eog
authors.initials: GE
authors.lastname: Ji
authors.forename: Jung-Sook
authors.initials: JS
authors.lastname: Kang
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D021381:Protein Transport; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005419:Flavonoids; D008077:Lipoproteins, LDL; D050791:STAT Transcription Factors; D016159:Tumor Suppressor Protein p53; C099252:oxidized low density lipoprotein; D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases