MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation.
A senescent phenotype in endothelial cells is associated with increased apoptosis, reduced endothelial nitric oxide synthase (eNOS) and inflammation, which are implicated in arterial dysfunction and disease in humans. We tested the hypothesis that changes in microRNAs are associated with a senescent phenotype in human aortic endothelial cells (HAEC). Compared with early-passage HAEC, late-passage HAEC had a reduced proliferation rate and increased staining for senescence-associated beta-galactosidase and the tumor suppressor p16(INK4a). Late-passage senescent HAEC had reduced expression of proliferation-stimulating/apoptosis-suppressing miR-21, miR-214 and miR-92 and increased expression of tumor suppressors and apoptotic markers. eNOS-suppressing miR-221 and miR-222 were increased and eNOS protein and eNOS activation (phosphorylation at serine1177) were lower in senescent HAEC. Caveolin-1 inhibiting miR-133a was reduced and caveolin-1, a negative regulator of eNOS activity, was elevated in senescent HAEC. Inflammation-repressing miR-126 was reduced and inflammation-stimulating miR-125b was increased, whereas inflammatory proteins were greater in senescent HAEC. Development of a senescent arterial endothelial cell phenotype featuring reduced cell proliferation, enhanced apoptosis and inflammation and reduced eNOS is associated with changes in miRNAs linked to the regulation of these processes. Our results support the hypothesis that miRNAs could play a critical role in arterial endothelial cell senescence.
Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO 80309, United States. catarina.rippe@med.lu.se
Catarina
C
Rippe
Mark
M
Blimline
Katherine A
KA
Magerko
Brooke R
BR
Lawson
Thomas J
TJ
LaRocca
Anthony J
AJ
Donato
Douglas R
DR
Seals
D001025:Aortitis / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018932:Chemokine CCL2; D035683:MicroRNAs; D019010:Vascular Cell Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; D020169:Caspases