Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, No. 361, Zhongshan East Rd, Shijiazhuang, 050017, China.
Circ Res. 2012 Aug 31;111(6):697-707. doi: 10.1161/CIRCRESAHA.112.272013. Epub 2012 Jul 12.
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.
To investigate how SM22α disruption promotes ROS production and to characterize the underlying mechanisms.
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.
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.
我们已经证明，平滑肌 22α（SM22α）通过阻断血管平滑肌细胞（VSMCs）和受损动脉中的 Ras-ERK1/2 信号来抑制细胞增殖。最近的研究表明，SM22α 的破坏可以通过激活活性氧物质（ROS）介导的 NF-κB 途径独立促进动脉炎症。然而，SM22α 控制 ROS 产生的机制尚未得到描述。
研究 SM22α 破坏如何促进 ROS 产生，并阐明潜在的机制。
通过二氢乙啶染色超氧化物和 TBA 测定法分别测量 ROS 水平。我们表明，SM22α 的下调和磷酸化与血管紧张素（Ang）II 诱导的大鼠和人 VSMCs 中 ROS 产生增加有关。Ang II 通过依赖于 Ang II 类型 1 受体-PKCδ 途径的方式诱导 SM22α 在丝氨酸 181 处的磷酸化。磷酸化的 SM22α 通过 2 种不同的途径激活蛋白激酶 C（PKC）δ-p47phox 轴：（1）在 Ang II 刺激的早期，PKCδ 从 SM22α 上分离，并转而与 p47phox 结合；（2）通过诱导肌动蛋白细胞骨架动态，加速 SM22α 通过泛素-蛋白酶体降解，增强 PKCδ 膜易位，在后期氧化应激中。抑制 SM22α 磷酸化可消除 Ang II 激活的 PKCδ-p47phox 轴，并抑制 VSMCs 的体外和体内肥大和增生，同时减少 ROS 产生。
这些发现表明，SM22α 的破坏在血管氧化应激中起关键作用。PKCδ 介导的 SM22α 磷酸化是肌动蛋白细胞骨架重塑与氧化应激之间的新联系，可能是开发心血管疾病新疗法的潜在靶点。
