Nup93-Mediated RNA Alternative Splicing Associated With Diabetic Atherosclerosis

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 analyze average signals of all cells overlook the importance of spatial information, although 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 analyze proteins in vascular smooth muscle tissues and atherosclerotic plaques obtained from a mouse 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 in cell models. Our findings 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.