Human SSA-lncWDR59 to reduce atherogenic adipose tissue and plaque progression
Z Abedi Kichi, M Bianchini, A Jung, S Mohanta, F M Farina, V Triantafyllidou, J Pelisek, M Vacca, M D Eusanio, D Santovito, A Bartelt, C Weber, L NatarelliAbstract
Background
Adipose tissue (AT) is a key regulator of systemic metabolism and immunity, and dysfunctional visceral AT (VAT) drives cardiometabolic disease through chronic inflammation and metabolic dysregulation. Current treatments primarily rely on lipid-lowering agents and weight loss strategies, which lack tissue specificity and can cause relevant side effects. Emerging evidence supports non-coding RNAs as more precise therapeutic targets; however, direct anti-miRNA approaches are limited by rapid degradation and unwanted immune activation. Here, we propose a dissociation therapy based on a human selective site antagonist (hSSA) that prevents miR-103 binding to the atheroprotective long non-coding RNA (lncRNA) lncWDR59. By preserving lncWDR59 function, this strategy is designed to attenuate atherosclerotic plaque progression and pathological AT expansion in mice and humans, where lncWDR59 activity is conserved.
Methods
Apoe−/− mice were fed a Western diet for 12 weeks and then treated via tail vein injections with a murine SSA-lncWDR59 construct or control for 4 weeks (n=12). In vitro, human visceral adipocytes (HA-v) and primary human aortic endothelial cells (HAoECs) were exposed to oxLDL and treated with hSSA-lncWDR59. Adipocyte remodeling, mitochondrial function, inflammatory activation, and DNA damage were assessed by qPCR, a whole-tissue RNA-FISH approach, immunofluorescence, and Seahorse metabolic assays. Bulk RNA-seq was performed in HA-v (n=3). Visceral AT from patients with cardiometabolic diseases was analyzed to correlate miR-103 and human lncWDR59 levels with markers of proliferation and DNA damage.
Results
In Apoe−/− mice, SSA-lncWDR59 restored lncWDR59 expression in ECs and VAT, reduced body weight gain, adipocyte hypertrophy, DNA damage, inflammatory markers, and macrophage infiltration, and decreased atherosclerotic plaque burden and AT mass without altering circulating lipid levels. In HA-v, hSSA-lncWDR59 normalized adipocyte differentiation and proliferation, dampened inflammatory responses, improved mitochondrial respiration, and reduced DNA damage. In macrovascular ECs, hSSA-lncWDR59 enhanced endothelial function by promoting controlled proliferation and limiting inflammation and genomic injury. RNA-seq analysis revealed a broad transcriptomic reprogramming, with enrichment of mitochondrial, metabolic, and anti-inflammatory pathways. In human AT, miR-103 and lncWDR59 showed an inverse correlation, whereby higher miR-103 levels were associated with increased proliferation and DNA damage, supporting their functional interplay in cardiometabolic disease.
Conclusions
Selective disruption of the miR-103:lncWDR59 interaction by hSSA-lncWDR59 mitigates pro-atherogenic AT remodeling and atherosclerotic plaque progression, without affecting systemic lipid levels. This dissociation-based, lncRNA-preserving strategy offers a novel therapeutic avenue for the treatment of cardiovascular and metabolic diseases.