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Phosphorylation of Smooth Muscle 22 Alpha Facilitates Angiotensin II-Inducted ROS Production via Activation of 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.
MedLine Citation:
PMID:  22798525     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Rationale: We have demonstrated that SM22α 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 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 and Results: ROS level was measured by dihydroethidium (DHE) staining for superoxide and TBA assay for malondialdehyde (MDA), respectively. We showed that down-regulation 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 AT1R-PKCδ pathway-dependent manner. Phosphorylated SM22α activated PKCδ-p47phox axis via two distinct pathways: 1) disassociation of PKCδ from SM22α, and in turn binding to p47phox, in early stage of Ang II stimulation; 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 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.
Authors:
Pin Lv; Sui-Bing Miao; Ya-Nan Shu; Li-Hua Dong; George Liu; Xiao-Li Xie; Min Gao; Yu-Can Wang; Ya-Juan Yin; Xiao-Juan Wang; Mei Han
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-12
Journal Detail:
Title:  Circulation research     Volume:  -     ISSN:  1524-4571     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Institute of Basic Medicine;
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