Common Genes Between Hyperlipidemia and Aortic Dissection and Their Regulatory Mechanisms

Hyperlipidemia is a potential risk factor for aortic dissection (AD), a severe cardiovascular emergency with high mortality. However, the common molecular mechanisms linking these 2 conditions remain poorly understood. This study aimed to identify common hub genes and elucidate their regulatory mechanisms in both hyperlipidemia and AD.

Transcriptome sequencing of dissected and normal ascending aorta tissues was performed to identify differentially expressed genes (DEGs) associated with AD. DEGs related to hyperlipidemia were analyzed using publicly available datasets. Common hub genes were identified through external dataset validation, protein-protein interaction (PPI) network analysis, immune infiltration assessment, transcription factor (TF) prediction, and drug interaction analysis. Functional validation was conducted in human aortic smooth muscle cells (HASMCs) subjected to angiotensin II (AngII) stimulation, utilizing lentivirus-mediated gene knockdown and overexpression, CCK-8 assay, flow cytometry, Transwell migration assay, and ELISA.

Based on the transcriptome sequencing data and publicly available datasets, 99 common DEGs were identified between the 2 diseases. Further external dataset validation revealed that only PIP5K1C, IFI44L, SUPT6H, and CHD3 were differentially expressed in the training and validation datasets for the 2 diseases and IFI44L was adopted as a hub gene. This gene had a high performance for the diagnosis of both diseases (AUC > 0.8) and was positively correlated with M1 macrophages in the 2 diseases. Experimental validation in HASMCs demonstrated that AngII treatment modulated IFI44L expression. IFI44L knockdown exacerbated AngII-induced reductions in cell viability, increased apoptosis, enhanced cell migration, and elevated pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) levels, whereas IFI44L overexpression attenuated these effects. IFI44L expression was positively correlated with M1 macrophage infiltration in both conditions.

IFI44L is a crucial common gene linking hyperlipidemia and AD, influencing vascular cell dysfunction and inflammatory responses via macrophage-related pathways. These findings highlight IFI44L as a potential diagnostic biomarker and therapeutic target for both diseases.