title: Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice.
abstract: The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD(+/+)) and manganese SOD heterozygous haploinsufficient (MnSOD(+/-)) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16(ink4a), a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD(+/+) and MnSOD(+/-) mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD(+/+) and MnSOD(+/-) mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD(+/+) mice but significantly impaired endothelial function in MnSOD(+/-) mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota;
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Roos
authors.forename: Michael
authors.initials: M
authors.lastname: Hagler
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Elise A
authors.initials: EA
authors.lastname: Oehler
authors.forename: Arman
authors.initials: A
authors.lastname: Arghami
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001021:Aortic Valve / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D057895:Haploinsufficiency; D006579:Heterozygote; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D014158:Transcription, Genetic; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D002118:Calcium; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase; D037761:Sirtuins; D013482:Superoxide Dismutase; D014665:Vasodilator Agents; D000099156:Superoxide Dismutase 2
keywords: aging; aorta; aortic valve; endothelial function; mitochondrial oxidative stress