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
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.
- Received April 27, 2012.
- Accepted July 11, 2012.
- Copyright © 2012, American Heart Association