MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation |
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Authors: | Rippe Catarina Blimline Mark Magerko Katherine A Lawson Brooke R LaRocca Thomas J Donato Anthony J Seals Douglas R |
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Affiliation: | Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO 80309, United States |
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Abstract: | 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 p16INK4a. 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. |
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Keywords: | DAPI, 4&prime ,6&prime -diamidino-2-phenylindole hydrochloride staining eNOS, endothelial nitric oxide synthase GAPDH, glyceraldehyde-3-phosphate dehydrogenase HAEC, human aortic endothelial cells HUVEC, human umbilical vein endothelial cells JNK1, c-Jun NH2-terminal kinase miRNA, microRNA MCP-1, monocyte chemotactic protein-1 NO, nitric oxide peNOS, phosphorylated endothelial nitric oxide synthase PTEN, Phosphatase and tensin homolog PDL, population doubling SA-β-gal, Senescence-associated beta-galatosidase VCAM-1, vascular cell adhesion molecule-1 |
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