Overexpressed long noncoding RNA CPS1‐IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin‐1β expression via HIF1 transcriptional activity

Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed to examine the effects of long noncoding RNA CPS1 intronic transcript 1 (CPS1-IT) on PAH in rat models of obstructive sleep apnea (OSA) through regulating interleukin (IL)-1β expression. The OSA models were induced in rats, for determination of the CPS1-IT expression. The binding of CPS1-IT and hypoxia-inducible factor 1 (HIF1) was verified. To analyze the effects of CPS1-IT on PAH, the overexpression vector of CPS1-IT and HIF1, shRNA against IL-1β and pyrrolidine dithiocarbamate (PDTC, inhibitor of the NF-κB signaling pathway) were injected into rat models, respectively. The blood pressure and activity of biochemical indicators including nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), and lipid peroxide (LPO) were assessed. The expression of IL-1β, HIF1, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and fibronectin (FN) was determined. The relationship of CPS1-IT to IL-1β and NF-κB was evaluated. CPS1-IT was downregulated in the OSA rat model. Overexpressed CPS1-IT increased the activity of NO, NOS, and SOD as well as α-SMA expression, whereas decreasing LPO activity and expression of PCNA and FN, whereby PAH was suppressed. Notably, overexpressed CPS1-IT reduced IL-1β expression through NF-κB signaling pathway via inhibiting the HIF1 transcriptional activity, suggesting a mechanism affecting PAH. To conclude, overexpressed CPS1-IT alleviated PAH in OSA by reducing IL-1β expression, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway. K E Y W O R D S hypoxia-inducible factor 1, interleukin-1β, long noncoding RNA CPS1 intronic transcript 1, nuclear factor-κB, obstructive sleep apnea, pulmonary arterial hypertension, transcriptional activity Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1β expression via HIF1 transcriptional activity.

SOD2 ameliorates pulmonary hypertension in a murine model of sleep apnea via suppressing expression of NLRP3 in CD11b+ cells

“…It has been reported that in OSA, the expression of IL-1β increased and the NF-kB pathway was activated, along with endothelial dysfunction induced by hypoxia/normoxia, all of which are synergistic with the formation and development of OSA [35]. Reduced IL-1β expression alleviated PH in OSA, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway [36]. Moreover, reduced mitochondria-derived reactive oxygen species (ROS) production and increased SOD-2 activity, resulting in the suppression of NLRP3 inflammasome-mediated IL-1β secretion.…”

Interleukin-1β in Multifactorial Hypertension: Inflammation, Vascular Smooth Muscle Cell and Extracellular Matrix Remodeling, and Non-Coding RNA Regulation

“…In addition to the effects on SAH, a recent study showed that overexpression of lncRNA Carbamoyl-phosphate synthetase 1-Intronic Transcript (CPS1-IT) was associated with reduced PH and lowered IL-1β in a mouse model of sleep apnea, likely through a mechanism involving the downregulation of HIF1 [17]. miR-340-5p was also shown to have a preventative role in the development of PH.…”

“…For instance, recent reports suggest that IL-1β not only participates in the pro-inflammatory response in the vessels, it also influences vascular smooth muscle cell (VSMC) phenotype and functions and vascular remodeling in multiple types of hypertension through inflammatory-dependent or independent mechanisms [16]. In addition, another new avenue of research in this area is related to the regulation of IL-1β by non-coding RNAs (ncRNAs) in hypertension [17,18]. These new findings also suggest that analogous regulatory mechanisms may be involved in the pathogenesis of various hypertensive disorders.…”

Epigenetic Alterations in Pediatric Sleep Apnea

“…In an adult rat model of OSA, decreased expression of lncRNA CPS1-intronic transcript was linked to pulmonary artery hypertension, and exogenous overexpression of lncRNA CPS1-IT alleviated hypertension through decreased IL-1β expression via inhibition of HIF-1 transcriptional activity and the NF-kβ signaling pathway 94 . A recent study by Zhou et al 95 found that lncRNA XIST promotes inflammation through the reduction of glucocorticoid receptor alpha in the adenoids of children with OSA.…”