Combined treatment of hydroxytyrosol with carbon monoxide-releasing molecule-2 prevents TNF α-induced vascular endothelial cell dysfunction through NO production with subsequent NFκB inactivation.
This study investigated the atheroprotective properties of olive oil polyphenol, hydroxytyrosol (HT), in combination with carbon monoxide-releasing molecule-2 (CORM-2) that acts as a carbon monoxide donor using vascular endothelial cells (VECs). Our results showed that CORM-2 could strengthen the cytoprotective and anti-apoptotic effects of HT against TNFα-induced cellular damage by enhancing cell survival and the suppression of caspase-3 activation. While HT alone attenuated NFκBp65 phosphorylation and IκBα degradation triggered by TNFα in a dose-dependent manner, combined treatment of HT with CORM-2 but not iCORM-2 nearly completely blocked these TNFα effects. Furthermore, combined action of both compounds results in the inhibition of NFκB nuclear translocation. Results also indicate that both compounds time-dependently increased eNOS phosphorylation levels and the combination of HT with CORM-2 was more effective in enhancing eNOS activation and NO production in VECs. The NOS inhibitor, L-NMMA, significantly suppressed the combined effects of HT and CORM-2 on TNFα-triggered NFκBp65 and IκBα phosphorylation as well as decreased cell viability. Together, these data suggest that carbon monoxide-dependent regulation of NO production by the combination of HT with CORM-2 may provide a therapeutic benefit in the treatment of endothelial dysfunction and atherosclerosis.
Faculty of Life and Environment Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Houda
H
Zrelli
Che Wei
CW
Wu
Nahla
N
Zghonda
Hidehisa
H
Shimizu
Hitoshi
H
Miyazaki
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000378:metabolism; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000069463:Olive Oil; D009942:Organometallic Compounds / Q000494:pharmacology*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010938:Plant Oils / Q000737:chemistry; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D000069463:Olive Oil; D009942:Organometallic Compounds; D010938:Plant Oils; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; C005975:3,4-dihydroxyphenylethanol; D009569:Nitric Oxide; D002248:Carbon Monoxide; D053148:Caspase 3; D010626:Phenylethyl Alcohol