Multi-omics analysis identifies the super-enhancer-driven gene NPW in left-sided obstructive lesions-associated cardiac remodeling

Abstract

Left-sided obstructive lesions (LSOLs), represented by coarctation of the aorta (CoA), cause persistent vascular pathology and pressure overload that can lead to pathological cardiac remodeling. However, the epigenetic changes associated with local vascular abnormalities and ventricular remodeling remain incompletely understood. We performed H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) in paired aortic tissues from patients with CoA to characterize region-associated super-enhancer (SE) landscapes and transcriptional alterations. Integrated multi-omics analysis, together with single-cell RNA sequencing (scRNA-seq) from LSOLs patients, identified neuropeptide W (NPW) as a SE-associated candidate. c-JUN CUT&RUN-qPCR showed AP-1 enrichment at successfully amplified NPW-associated SE regions (Peak1). In primary smooth muscle cells (SMCs), broad BET inhibition or NPW silencing was associated with reduced contractile-marker expression, whereas exogenous NPW attenuated angiotensin II-induced cardiomyocyte hypertrophy in vitro. Plasma NPW levels were lower in patients with CoA and were associated with echocardiographic indices of remodeling. These findings identify NPW as a SE-associated candidate pathway in CoA and provide supportive evidence for broader relevance to LSOLs-associated cardiac remodeling.