DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation

作者：Wang, Litao; Wu, Lin; Du, Yuxin; Wang, Xiang; Yang, Bingsheng; Guo, Shuai; Zhou, Yuan; Xu, Yiming; Yang, Shuofei^*; Zhang, Yingmei^*; Ren, Jun^*

来源：Redox Biology, 2023, 67: 102893.

DOI：10.1016/j.redox.2023.102893

• DNA-PKcs
• Vascular remodeling
• Drp1
• Mitochondrial fragmentation
• Hypertension

Background: 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.Methods: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcs Delta VSMC) 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.Results: 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-PKcsfl/fl) and DNA-PKcs Delta VSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcs Delta VSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNAPKcs 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 Drp1S616, 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.Conclusion: 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 Drp1S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

• 单位
  广州医学院; 北京大学; 南方医科大学; 复旦大学; 上海交通大学