A regulatory role of novel long non-coding RNA, BAZ1A-AS1, in vascular smooth muscle cell functions during neointima formation in human saphenous veins

IntroductionThe human saphenous vein (SV) graft remains the most commonly used conduit for coronary artery bypass grafting (CABG) surgery; however, approximately 50% of SV grafts fail within 10 years, primarily due to neointima formation. Previously, by multiomics analysis in human vein tissues, we reported that dynamic transcriptomic and proteomic changes occur during neointima formation in human veins. The present study sought to elucidate the molecular mechanisms underlying neointima formation in human SV, focusing on the functional roles of novel candidate long non-coding RNAs (lncRNAs). Methods and ResultsUsing an ex vivo model of human SV disease, in which freshly obtained SV segments were maintained under tissue culture conditions, we performed bulk RNA sequencing on SV tissues with and without neointima formation. Transcriptomic profiling revealed pronounced vascular smooth muscle cell (VSMC) de-differentiation, inflammation, and proliferation as dominant molecular signatures associated with neointima formation. Among differentially expressed lncRNAs, we identified a previously uncharacterized transcript, Bromodomain Adjacent to Zinc Finger A1 antisense 1 (BAZ1A-AS1), and its predicted cis-regulatory partner gene BAZ1A, as markedly upregulated during neointima development and predominantly enriched in VSMCs. Exposure of VSMCs to inflammatory (TNF) or DNA-damaging (UV) stimuli further induced the expression of both BAZ1A-AS1 and BAZ1A, and silencing of either BAZ1A-AS1 or BAZ1A significantly attenuated VSMC proliferation and migration, accompanied by reduced expression of the proliferation marker CCND1, suggesting that this lncRNA-gene dyad plays a critical role in mediating VSMC phenotypic switching in response to inflammatory and genotoxic stress. Consistently, in vivo deletion of Baz1a gene in mice also attenuated neointima formation in a carotid artery ligation model. ConclusionsWe identified a human-specific lncRNA, BAZ1A-AS1, and its predicted cis-regulatory gene, BAZ1A, as key molecular regulators of neointima formation in human SV. These findings highlight the BAZ1A-AS1/BAZ1A axis as a potential therapeutic target for preventing SV graft failure following CABG.