Novel Long Noncoding RNA <i>HEAT4</i> Affects Monocyte Subtypes, Reducing Inflammation and Promoting Vascular Healing.

Abstract

Activation of the immune system contributes to cardiovascular diseases. The role of human-specific long noncoding RNAs in cardioimmunology is poorly understood. Single-cell sequencing in peripheral blood mononuclear cells revealed a novel human-specific long noncoding RNA called <i>HEAT4</i> (heart failure-associated transcript 4). <i>HEAT4</i> expression was assessed in several in vitro and ex vivo models of immune cell activation, as well as in the blood of patients with heart failure (HF), acute myocardial infarction, or cardiogenic shock. The transcriptional regulation of <i>HEAT4</i> was verified through cytokine treatment and single-cell sequencing. Loss-of-function and gain-of-function studies and multiple RNA-protein interaction assays uncovered a mechanistic role of <i>HEAT4</i> in the monocyte anti-inflammatory gene program. <i>HEAT4</i> expression and function was characterized in a vascular injury model in NOD.CB17-Prkdc scid/Rj mice. <i>HEAT4</i> expression was increased in the blood of patients with HF, acute myocardial infarction, or cardiogenic shock. <i>HEAT4</i> levels distinguished patients with HF from people without HF and predicted all-cause mortality in a cohort of patients with HF over 7 years of follow-up. Monocytes, particularly anti-inflammatory CD16⁺ monocytes, which are increased in patients with HF, are the primary source of <i>HEAT4</i> expression in the blood. <i>HEAT4</i> is transcriptionally activated by treatment with anti-inflammatory interleukin-10. <i>HEAT4</i> activates anti-inflammatory and inhibits proinflammatory gene expression. Increased <i>HEAT4</i> levels result in a shift toward more CD16⁺ monocytes. <i>HEAT4</i> binds to S100A9, causing a monocyte subtype switch, thereby reducing inflammation. As a result, <i>HEAT4</i> improves endothelial barrier integrity during inflammation and promotes vascular healing after injury in mice. These results characterize a novel endogenous anti-inflammatory pathway that involves the conversion of monocyte subtypes into anti-inflammatory CD16⁺ monocytes. The data identify a novel function for the class of long noncoding RNAs by preventing protein secretion and suggest long noncoding RNAs as potential targets for interventions in the field of cardioimmunology.