title: Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function.
abstract: OBJECTIVE
  Age-related aortic stiffness is an independent risk factor for cardiovascular diseases. Although oxidative stress is implicated in aortic stiffness, the underlying molecular mechanisms remain unelucidated. Here, we examined the source of oxidative stress in aging and its effect on smooth muscle cell (SMC) function and aortic compliance using mutant mouse models.
  
  
  RESULTS
  Pulse wave velocity, determined using Doppler, increased with age in superoxide dismutase 2 (SOD2)+/- but not in wild-type, p47phox-/- and SOD1+/- mice. Echocardiography showed impaired cardiac function in these mice. Increased collagen I expression, impaired elastic lamellae integrity, and increased medial SMC apoptosis were observed in the aortic wall of aged SOD2+/- versus wild-type (16-month-old) mice. Aortic SMCs from aged SOD2+/- mice showed increased collagen I and decreased elastin expression, increased matrix metalloproteinase-2 expression and activity, and increased sensitivity to staurosporine-induced apoptosis versus aged wild-type and young (4-month-old) SOD2+/- mice. Smooth muscle α-actin levels were increased with age in SOD2+/- versus wild-type SMCs. Aged SOD2+/- SMCs had attenuated insulin-like growth factor-1-induced Akt and Forkhead box O3a phosphorylation and prolonged tumor necrosis factor-α-induced Jun N-terminal kinase 1 activation. Aged SOD2+/- SMCs had increased mitochondrial superoxide but decreased hydrogen peroxide levels. Finally, dominant-negative Forkhead box O3a overexpression attenuated staurosporine-induced apoptosis in aged SOD2+/- SMCs.
  
  
  CONCLUSIONS
  Mitochondrial oxidative stress over a lifetime causes aortic stiffening, in part by inducing vascular wall remodeling, intrinsic changes in SMC stiffness, and aortic SMC apoptosis.
authors.affiliation: McAllister Heart Institute, Department of Medicine, 125 MacNaider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7005, USA.
authors.forename: Rui-Hai
authors.initials: RH
authors.lastname: Zhou
authors.forename: Aleksandr E
authors.initials: AE
authors.lastname: Vendrov
authors.forename: Igor
authors.initials: I
authors.lastname: Tchivilev
authors.forename: Xi-Lin
authors.initials: XL
authors.lastname: Niu
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Molnar
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Carter
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tong
authors.forename: George A
authors.initials: GA
authors.lastname: Stouffer
authors.forename: Nageswara R
authors.initials: NR
authors.lastname: Madamanchi
authors.forename: Marschall S
authors.initials: MS
authors.lastname: Runge
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001018:Aortic Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017209:Apoptosis; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003187:Compliance; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006861:Hydrogen Peroxide / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D018384:Oxidative Stress; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011673:Pulsatile Flow; D013318:Stroke Volume; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D018617:Ultrasonography, Doppler, Pulsed; D014664:Vasodilation; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D000099156:Superoxide Dismutase 2
chemical_list: D000199:Actins; D024042:Collagen Type I; D004549:Elastin; D051858:Forkhead Transcription Factors; D006861:Hydrogen Peroxide; D007334:Insulin-Like Growth Factor I; D020778:Matrix Metalloproteinase 2; D048055:Mitogen-Activated Protein Kinase 8; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C558396:Acta2 protein, mouse; C519530:insulin-like growth factor-1, mouse; C000606291:Sod1 protein, mouse; C060505:neutrophil cytosolic factor 1; C522362:Mmp2 protein, mouse