Phosphorylation of smooth muscle 22α facilitates angiotensin II-induced ROS production via activation of the PKCδ-P47phox axis through release of PKCδ and actin dynamics and is associated with hypertrophy and hyperplasia of vascular smooth muscle cells in vitro and in vivo.
Circ Res
; 111(6): 697-707, 2012 Aug 31.
Article
em En
| MEDLINE
| ID: mdl-22798525
ABSTRACT
RATIONALE We have demonstrated that smooth muscle (SM) 22α inhibits cell proliferation via blocking Ras-ERK1/2 signaling in vascular smooth muscle cells (VSMCs) and in injured arteries. The recent study indicates that SM22α disruption can independently promote arterial inflammation through activation of reactive oxygen species (ROS)-mediated NF-κB pathways. However, the mechanisms by which SM22α controls ROS production have not been characterized. OBJECTIVE:
To investigate how SM22α disruption promotes ROS production and to characterize the underlying mechanisms. METHODS ANDRESULTS:
ROS level was measured by dihydroethidium staining for superoxide and TBA assay for malondialdehyde, respectively. We showed that downregulation and phosphorylation of SM22α were associated with angiotensin (Ang) II-induced increase in ROS production in VSMCs of rats and human. Ang II induced the phosphorylation of SM22α at Serine 181 in an Ang II type 1 receptor-PKCδ pathway-dependent manner. Phosphorylated SM22α activated the protein kinase C (PKC)δ-p47phox axis via 2 distinct pathways (1) disassociation of PKCδ from SM22α, and in turn binding to p47phox, in the early stage of Ang II stimulation; and (2) acceleration of SM22α degradation through ubiquitin-proteasome, enhancing PKCδ membrane translocation via induction of actin cytoskeletal dynamics in later oxidative stress. Inhibition of SM22α phosphorylation abolished the Ang II-activated PKCδ-p47phox axis and inhibited the hypertrophy and hyperplasia of VSMCs in vitro and in vivo, accompanied with reduction of ROS generation.CONCLUSIONS:
These findings indicate that the disruption of SM22α plays pivotal roles in vascular oxidative stress. PKCδ-mediated SM22α phosphorylation is a novel link between actin cytoskeletal remodeling and oxidative stress and may be a potential target for the development of new therapeutics for cardiovascular diseases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Angiotensina II
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Actinas
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Espécies Reativas de Oxigênio
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NADPH Oxidases
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Miócitos de Músculo Liso
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Proteína Quinase C-delta
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Proteínas dos Microfilamentos
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Proteínas Musculares
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article