在体内和体外条件下,平滑肌22α磷酸化可通过释放PKCδ和影响肌动蛋白动力学而激活PKCδ-P47phox轴从而促进血管紧张素Ⅱ诱导性ROS生成,并且与血管平滑肌细胞肥大和增生有关
Han, M.; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361, Zhongshan East Rd, Shijiazhuang, 050017, China; email:hanmei@hebmu.edu.cn
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 and Results: 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-p47 phox axis via 2 distinct pathways: (1) disassociation of PKCδ from SM22α, and in turn binding to p47 phox, 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-p47 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. © 2012 American Heart Association, Inc
Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361, Zhongshan East Rd, Shijiazhuang, 050017, China
来源: Scopus
- 您可能感兴趣的文章
-