title: Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells.
abstract: Endothelial dysfunction precedes cardiovascular disease and is accompanied by mitochondrial dysfunction. Here we tested the hypothesis that diesel exhaust particulate extracts (DEPEs), prepared from a truck run at different speeds and engine loads, would inhibit genomic estrogen receptor activation of nuclear respiratory factor-1 (NRF-1) transcription in human umbilical vein endothelial cells (HUVECs). Additionally, we examined how DEPEs affect NRF-1-regulated TFAM expression and, in turn, Tfam-regulated mtDNA-encoded cytochrome c oxidase subunit I (COI, MTCO1) and NADH dehydrogenase subunit I (NDI) expression as well as cell proliferation and viability. We report that 17β-estradiol (E(2)), 4-hydroxytamoxifen (4-OHT), and raloxifene increased NRF-1 transcription in HUVECs in an ER-dependent manner. DEPEs inhibited NRF-1 transcription, and this suppression was not ablated by concomitant treatment with E(2), 4-OHT, or raloxifene, indicating that the effect was not due to inhibition of ER activity. While E(2) increased HUVEC proliferation and viability, DEPEs inhibited viability but not proliferation. Resveratrol increased NRF-1 transcription in an ER-dependent manner in HUVECs, and ablated DEPE inhibition of basal NRF-1 expression. Given that NRF-1 is a key nuclear transcription factor regulating genes involved in mitochondrial activity and biogenesis, these data suggest that DEPEs may adversely affect mitochondrial function leading to endothelial dysfunction and resveratrol may block these effects.
authors: Department of Biochemistry & Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Kathleen A
authors: KA
authors: Mattingly
authors: Carolyn M
authors: CM
authors: Klinge
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004336:Drug Antagonism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004958:Estradiol / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics* / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity*; D020849:Raloxifene Hydrochloride / Q000633:toxicity; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects*; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D052638:Particulate Matter; D013267:Stilbenes; D001335:Vehicle Emissions; D013629:Tamoxifen; C016601:afimoxifene; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D003576:Electron Transport Complex IV; D000077185:Resveratrol