Abstract Body: Atherosclerosis, the principal driver of cardiovascular disease, arises from dysregulated lipid metabolism and maladaptive immune responses that sustain chronic inflammation within the arterial wall and promote plaque formation. Elucidating the molecular mechanisms that maintain this persistent inflammatory state may uncover new therapeutic targets to limit plaque progression. Over the past decade, advances in genomics have revealed long noncoding RNAs (lncRNAs) as key regulators of genome organization and gene expression.
We identified the conserved lncRNA, CARINH, as highly expressed in circulating monocytes and plaque macrophages in human clinical samples and mouse models of atherosclerosis. CARINH is transcribed antisense to IRF1 and highly expressed in plaque macrophages, where its expression positively correlates with interferon (IFN)-stimulated genes, including IRF1, a key regulator of type I IFN signaling and inflammatory and metabolic pathways implicated in atherogenesis. Consistently, exposure of primary human macrophages to atherogenic oxidized LDL or IFN-β induced CARINH and IRF1 expression, suggesting shared regulation under pro-atherogenic conditions. Silencing of CARINH using antisense oligonucleotides reduced IRF1 expression, leading to decreased lipid uptake, enhanced cholesterol efflux, and diminished secretion of type I and II IFNs.
In mice, Carinh exhibits conserved regulation and function in mouse macrophages, including co-expression with Irf1 and control of IFN and IFN-stimulated gene programs. To study its role in leukocytes during plaque progression, we generated a Carinh knockout mouse model and fed reconstituted Ldlr^–/– mice with bone marrow from Carinh ^–/–or WT mice a WD for 16 weeks. Mice with hematopoietic Carinh deficiency exhibited a ~30% reduction in aortic arch lesion area compared to controls, despite no differences in total cholesterol, body weight, circulating leukocytes, and neutrophil infiltration in lesions. Furthermore, Carinh deficient mice displayed increased macrophage content within lesions, while lipid accumulation and necrotic area were unaffected.

Together, our findings establish CARINH as a critical regulator of atherosclerosis at the intersection of IFN-driven immunity and lipid metabolism, highlighting conserved lncRNAs as promising therapeutic targets to dampen vascular inflammation and limit plaque progression.