Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
Department of Orthopedics, Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Redox Biol. 2023 Nov;67:102893. doi: 10.1016/j.redox.2023.102893. Epub 2023 Sep 16.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure.
Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcs) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment.
In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcs) and DNA-PKcs mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcs mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1, subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration.
Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.
DNA 依赖性蛋白激酶催化亚基（DNA-PKcs）是一种新型的线粒体功能障碍启动子，在心血管疾病的发病机制中发挥着重要作用。然而，DNA-PKcs 在血管紧张素 II（Ang II）诱导的血管重构中的作用及其机制仍不清楚。
采用大鼠主动脉平滑肌细胞（SMC）和血管平滑肌细胞特异性 DNA-PKcs 敲除（DNA-PKcs）小鼠来检测 DNA-PKcs 在血管重构中的作用及其机制。采用尾套法和遥测法监测小鼠血压。采用血管舒张评估来检测 DNA-PKcs 在血管功能中的作用。
在重构的小鼠胸主动脉中以及高血压患者的肾动脉中层，DNA-PKcs 表达升高，并伴有其从核内的细胞质易位，提示 DNA-PKcs 在血管重构中发挥作用。然后，我们给野生型（DNA-PKcs）和 DNA-PKcs 小鼠输注 Ang II 14 天，建立血管重构模型，结果显示 DNA-PKcs 小鼠通过抑制 VSMCs 的去分化，显示出血管重构的减弱。此外，VSMCs 中 DNA-PKcs 的缺失缓解了 Ang II 诱导的血管舒张功能障碍和高血压。机制研究表明，Ang II 诱导的细胞质 DNA-PKcs 与动力相关蛋白 1（Drp1）在其 TQ 基序相互作用，使 Drp1 磷酸化，进而促进线粒体碎片化和功能障碍以及活性氧（ROS）的产生。血管紧张素 II 1 型受体（AT1R）阻滞剂厄贝沙坦处理后，可降低 Ang II 处理后 VSMCs 和主动脉组织中 DNA-PKcs 的表达。
我们的数据表明，VSMCs 中的细胞质 DNA-PKcs 通过与 Drp1 在其 TQ 基序相互作用，并使 Drp1 磷酸化，导致线粒体碎片化，从而加速 Ang II 诱导的血管重构。针对 DNA-PKcs 的操作可能是治疗血管重构和高血压的一种有价值的治疗选择。
