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

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

doi:10.1016/j.redox.2023.102893

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

Redox Biol. 2023 Nov:67:102893. doi: 10.1016/j.redox.2023.102893. Epub 2023 Sep 16.

Authors

Litao Wang¹, Lin Wu¹, Yuxin Du¹, Xiang Wang¹, Bingsheng Yang², Shuai Guo³, Yuan Zhou⁴, Yiming Xu³, Shuofei Yang⁵, Yingmei Zhang⁶, Jun Ren⁷

Affiliations

¹ 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.
² Department of Orthopedics, Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
³ School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
⁴ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
⁵ Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: doctor_yangshuofei@163.com.
⁶ 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. Electronic address: zhang.yingmei@zs-hospital.sh.cn.
⁷ 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. Electronic address: ren.jun@zs-hospital.sh.cn.

Abstract

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^ΔVSMC) 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-PKcs^fl/fl) and DNA-PKcs^ΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcs^ΔVSMC 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^S616, 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 Drp1^S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

Keywords: DNA-PKcs; Drp1; Hypertension; Mitochondrial fragmentation; Vascular remodeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II* / metabolism
Animals
Catalytic Domain
DNA / metabolism
DNA-Activated Protein Kinase / genetics
DNA-Activated Protein Kinase / metabolism
Humans
Hypertension* / metabolism
Mice
Myocytes, Smooth Muscle / metabolism
Rats
Vascular Remodeling / physiology

Substances

Angiotensin II
DNA-Activated Protein Kinase
DNA