Nup93-Mediated RNA Alternative Splicing Associated with Diabetic Atherosclerosis

Xiaojing Yuan; Qilun Zhang; Jie Li; Zichen Zhang; Shandong Ye; Wei Wang; Wan Zhou

doi:10.1016/j.mcpro.2025.101029

Nup93-Mediated RNA Alternative Splicing Associated with Diabetic Atherosclerosis

Mol Cell Proteomics. 2025 Jul 7:101029. doi: 10.1016/j.mcpro.2025.101029. Online ahead of print.

Authors

Xiaojing Yuan¹, Qilun Zhang¹, Jie Li², Zichen Zhang³, Shandong Ye³, Wei Wang³, Wan Zhou⁴

Affiliations

¹ Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Department of Endocrinology and Laboratory for Diabetes, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
² Department of Endocrinology, The First Affiliated Hospital of USTC, Affiliated to Anhui Medical University, Hefei, Anhui, 230001, China.
³ Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
⁴ Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. Electronic address: zwan@ustc.edu.cn.

PMID: 40633766
DOI: 10.1016/j.mcpro.2025.101029

Abstract

Atherosclerosis, a life-threatening complication of diabetes mellitus (DM), significantly increases the mortality risk among diabetic patients. Vascular smooth muscle cells (VSMCs) not only constitute the core of atherosclerotic lesions but also serve as primary components of plaques. Although diabetes expedites this transformation process, the specific mechanism remains elusive. Traditional proteomic approaches that analyse average signals of all cells overlook the importance of spatial information, even though different cells within the same tissue exhibit distinct molecular characteristics during various stages of atherosclerosis progression. In this study, we employed spatial proteomic technology to comprehensively analyse proteins in vascular smooth muscle tissues and atherosclerotic plaques obtained from a mice model of atherosclerosis and DM complicated with arteriosclerosis. We also employed RNA sequencing technology to further investigate the changes in RNA alternative splicing in atherosclerosis and DM complicated with arteriosclerosis cell models. Our finding revealed the reduced expression of Nup93 within VSMCs under combined high glucose and ox-LDL stimulation, mimicking diabetic atherosclerotic stress. This reduction impairs the nuclear import of splicing regulators SRSF1 and SRSF3, leading to abnormal alternative splicing of SerpinE2, which in turn enhances its mRNA stability and promotes VSMCs proliferation. These results reveal a novel mechanistic axis whereby diabetic atherosclerotic stress drives VSMCs dysfunction through Nup93-mediated splicing dysregulation, offering new molecular targets for the treatment of diabetes-associated atherosclerosis.

Keywords: Atherosclerosis; Diabetes mellitus; Nup93; Proliferation; Spatial proteomic technology; Vascular smooth muscle cells.