Research Paper|Volume 12, Issue 21|pp 22174—22198

Nucleolar stress induces a senescence-like phenotype in smooth muscle cells and promotes development of vascular degeneration

Wenjing Zhang^1,², Wen Cheng³, Rosanna Parlato^4,⁵, Xiaosun Guo¹, Xiaopei Cui², Chaochao Dai^1,², Lei Xu⁶, Jiankang Zhu⁷, Min Zhu⁸, Kun Luo⁹, Wencheng Zhang³, Bo Dong¹⁰, Jianli Wang^1,¹¹, Fan Jiang^1,²

¹Department of Physiology and Pathophysiology, School of Basic Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
²Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
³Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
⁴Institute of Applied Physiology, University of Ulm, Ulm, Germany
⁵Institute of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany
⁶Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
⁷Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
⁸Department of Transplant Surgery, Qilu Hospital of Shandong University, Jinan, China
⁹Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
¹⁰Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
¹¹Current address: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China

Received: June 12, 2020Accepted: August 31, 2020Published: November 4, 2020

https://doi.org/10.18632/aging.104094

Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Senescence of smooth muscle cells (SMCs) has a crucial role in the pathogenesis of abdominal aortic aneurysm (AAA), a disease of vascular degeneration. Perturbation of cellular ribosomal DNA (rDNA) transcription triggers nucleolar stress response. Previously we demonstrated that induction of nucleolar stress in SMCs elicited cell cycle arrest via the ataxia-telangiectasia mutated (ATM)/ATM- and Rad3-related (ATR)-p53 axis. However, the specific roles of nucleolar stress in vascular degeneration remain unexplored. In the present study, we demonstrated for the first time that in both human and animal AAA tissues, there were non-coordinated changes in the expression of RNA polymerase I machinery components, including a downregulation of transcription initiation factor-IA (TIF-IA). Genetic deletion of TIF-IA in SMCs in mice (smTIF-IA^-/-) caused spontaneous aneurysm-like lesions in the aorta. In vitro, induction of nucleolar stress triggered a non-canonical DNA damage response, leading to p53 phosphorylation and a senescence-like phenotype in SMCs. In human AAA tissues, there was increased nucleolar stress in medial cells, accompanied by localized DNA damage response within the nucleolar compartment. Our data suggest that perturbed rDNA transcription and induction of nucleolar stress contribute to the pathogenesis of AAA. Moreover, smTIF-IA^-/- mice may be a novel animal model for studying spontaneous AAA-like vascular degenerations.