Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function.
Arterioscler Thromb Vasc Biol
; 32(3): 745-55, 2012 Mar.
Article
em En
| MEDLINE
| ID: mdl-22199367
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. METHODS ANDRESULTS:
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.CONCLUSION:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças da Aorta
/
Envelhecimento
/
Estresse Oxidativo
/
Miócitos de Músculo Liso
/
Mitocôndrias
/
Músculo Liso Vascular
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos