The long non-coding RNA Heat4 is upregulated in heart failure and decreases the immune response of non-classical monocytes. (14th October 2021)

• Record Type: Journal Article
• Authors: Kneuer, J; Meinecke, T; Weiss, R; Gaul, S; Haas, J; Meder, B; Garfias-Veitel, T; Von Haehling, S; Kogel, A; Keller, T; Speer, T; Thiele, H; Lurz, P; Laufs, U; Boeckel, J.-N
• Is Part Of: European heart journal. Volume 42(2021)Supplement 1
• Publication Date: 2021-10-14
• Subjects: Heart Failure; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab724.3298
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background and purpose: Activation of the immune system correlates with the severity and the prognosis of patients with heart failure (HF). This study aims to identify and characterize long non-coding RNAs (lncRNAs) as a potential mechanistic link between the pathophysiology of HF and the activation of the immune system. Methods and results: Next-generation sequencing (NGS) studies identified a 2.05-fold increase of the lncRNA Heat4 in the blood of patients with HF compared to controls, which was validated in a larger cohort (HF: N=63; Controls: N=38; p<0.05). Interestingly, the lncRNA Heat4 is encoded in the well-known immune receptor locus CD300, together with 8 CD300-receptors which are associated with activation of the immune system. To determine the cellular origin of Heat4 in blood, we performed MACS and identified Heat4 to be enriched in non-classical monocytes compared to classical monocytes (3.37-fold, p<0.05). The expression of Heat4 in non-classical monocytes was further validated by single-cell RNA sequencing. Overexpression of Heat4 in monocytes decreased levels of pro-inflammatory cytokines such as TNFα (38.6% reduction, p<0.05). Conversely, the knockdown of Heat4 resulted in elevated levels of pro-inflammatory cytokines, including IL6 (10.83-fold, p<0.05) and TNFα (4.14-fold, p<0.05). In a larger cohort including patients with HF, Heat4 was able to determine the prevalence of heart failure by AUC=0.734 (p<0.05). Moreover, in a 4-year follow-up of the same cohort, Heat4 predicted mortality by AUC=0.789 (HF: N=63, Dead=32; Controls: N=38, Dead=0; p<0.05). Conclusion: The long non-coding RNA Heat4 is elevated in the blood of HF patients. Mechanistically, Heat4 limits the extent of the inflammatory response of non-classical monocytes. Therefore, Heat4 may provide a regulatory link between inflammation and HF. Funding Acknowledgement: Type of funding sources: None.