title: Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats.
abstract: In rodents, moderate caloric restriction (CR) without malnutrition exerts significant cerebrovascular protective effects, improving cortical microvascular density and endothelium-dependent vasodilation, but the underlying cellular mechanisms remain elusive. To elucidate the persisting effects of CR on cerebromicrovascular endothelial cells (CMVECs), primary CMVECs were isolated from young (3 mo old) and aged (24 mo old) ad libitum-fed and aged CR F344xBN rats. We found an age-related increase in cellular and mitochondrial oxidative stress, which is prevented by CR. Expression and transcriptional activity of Nrf2 are both significantly reduced in aged CMVECs, whereas CR prevents age-related Nrf2 dysfunction. Expression of miR-144 was upregulated in aged CMVECs, and overexpression of miR-144 significantly decreased expression of Nrf2 in cells derived from both young animals and aged CR rats. Overexpression of a miR-144 antagomir in aged CMVECs significantly decreases expression of miR-144 and upregulates Nrf2. We found that CR prevents age-related impairment of angiogenic processes, including cell proliferation, adhesion to collagen, and formation of capillary-like structures and inhibits apoptosis in CMVECs. CR also exerts significant anti-inflammatory effects, preventing age-related increases in the transcriptional activity of NF-κB and age-associated pro-inflammatory shift in the endothelial secretome. Characterization of CR-induced changes in miRNA expression suggests that they likely affect several critical functions in endothelial cell homeostasis. The predicted regulatory effects of CR-related differentially expressed miRNAs in aged CMVECs are consistent with the anti-aging endothelial effects of CR observed in vivo. Collectively, we find that CR confers persisting anti-oxidative, pro-angiogenic, and anti-inflammatory cellular effects, preserving a youthful phenotype in rat cerebromicrovascular endothelial cells, suggesting that through these effects CR may improve cerebrovascular function and prevent vascular cognitive impairment.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center University of Pecs, Pecs, Hungary; anna-csiszar@ouhsc.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Department of Anatomy, MTA-PTE Lendulet Research Group, Medical School, University of Pecs, Pecs, Hungary;
authors.forename: Eszter
authors.initials: E
authors.lastname: Banki
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: Department of Pulmonology, Semmelweis University, Budapest, Hungary;
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Losonczy
authors.affiliation: Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center University of Pecs, Pecs, Hungary;
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
authors.affiliation: Department of Anatomy, MTA-PTE Lendulet Research Group, Medical School, University of Pecs, Pecs, Hungary;
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.affiliation: Oklahoma Medical Research Foundation, Arthritis and Clinical Immunology Research Program and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
authors.forename: Cory B
authors.initials: CB
authors.lastname: Giles
authors.affiliation: Oklahoma Medical Research Foundation, Arthritis and Clinical Immunology Research Program and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pathophysiology and Gerontology, Medical School and Szentagothai Research Center University of Pecs, Pecs, Hungary;
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D031204:Caloric Restriction; D002478:Cells, Cultured; D003433:Crosses, Genetic; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000276:immunology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D018836:Inflammation Mediators; C555034:MIRN144 microRNA, rat; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat
keywords: aging; angiogenesis; caloric restriction; dietary restriction; senescence