Abstract 4370671: TERRA Downregulation and Pathway Alterations in a Murine Model of Neurohormonal Heart Failure

Abstract

Heart failure (HF) remains a leading cause of mortality worldwide, exacerbated by age-related myocardial degeneration. Our prior work demonstrated that cardiomyocyte telomere shortening, a hallmark of myocardial aging, is driven by oxidative damage via NOX2 activity. Long non-coding telomeric repeat-containing RNA (TERRA), a key regulator of telomere homeostasis, may play a pivotal role in this process. In this study, we examined the contribution of myeloid NOX2 and TERRA dynamics in a neurohormonal HF mouse model using male mice (6–8 weeks old) subjected to unilateral nephrectomy, AngII infusion, and high-salt water for 6 weeks (ANS). Mice with myeloid-specific NOX2 knockout (LysM-NOX2-KO) were compared to littermate controls (Nox2 fl/fl LysM cre/wt vs Nox2 fl/fl LysM wt/wt ), as well as in wild-type C57BL/6J mice. Echocardiography showed preserved LVEF in Nox 2 KO mice (52% vs. 40%), despite similar elevated blood pressure. Telomere FISH confirmed shortening in both ANS groups. qPCR confirmed loss of NOX2 expression in KO hearts, alongside increased NOX4 and significantly elevated IL-6, suggesting compensatory proinflammatory remodelling. Importantly, TERRA transcripts from chromosomes 2, 18, and PAR regions were significantly downregulated in wild-type B6J mice following neurohormonal activation compared to Sham. These findings suggest that TERRA suppression is associated with stress-induced telomere dysfunction. KEGG enrichment analyses of downregulated genes revealed alterations in metabolic and circadian pathways (e.g., insulin signalling, cAMP, fatty acid degradation), while upregulated genes were enriched in PI3K-Akt, cytokine-cytokine receptor interaction, and ECM remodelling pathways—indicative of inflammatory and structural cardiac remodelling. Gene ontology analysis further highlighted dysregulation of contraction, ion transport, and cardiac conduction pathways. Collectively, these results underscore a role for TERRA downregulation in the molecular cascade of HF. Myeloid NOX2 deficiency appears protective, potentially via IL-6-mediated signalling, independent of hemodynamic load. Our findings reveal a complex interplay between oxidative stress, inflammation, and telomeric regulation, supporting NOX2 and TERRA as promising therapeutic targets in HF driven by myocardial aging.