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
Affiliations
Litao Wang
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
Lin Wu
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
Yuxin Du
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
Xiang Wang
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
Bingsheng Yang
Department of Orthopedics, Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Shuai Guo
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
Yuan Zhou
Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, 100191, China
Yiming Xu
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
Shuofei Yang
Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
Yingmei Zhang
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
Jun Ren
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; Corresponding author. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai, 200032, China.
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-PKcsΔVSMC) 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-PKcsΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcsΔVSMC 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 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.
