Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension

Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified ‘early’ and ‘late’ subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation. The circulating levels of several extracellular matrix proteins deregulated in decompensated RV subgroups were assessed in two independent cohorts of individuals with pulmonary arterial hypertension, revealing that NID1, C1QTNF1 and CRTAC1 predicted the development of a maladaptive RV state, as defined by magnetic resonance imaging parameters, and were associated with worse clinical outcomes. Our study provides a resource for subphenotyping RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction

Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRβ

RATIONALE: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored. OBJECTIVES: To elucidate the role of tyrosine kinase receptor inducing lncRNA (TYKRIL) as a regulator of p53/platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and to investigate its role in PAH. MEASUREMENTS AND MAIN RESULTS: Using RNAseq data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells (PASMCs) exposed to hypoxia and derived from IPAH patients. TYKRIL knockdown reversed the pro-proliferative (n=3) and anti-apoptotic (n=3) phenotype induced under hypoxic and IPAH conditions. Due to the poor species conservation of TYKRIL, ex-vivo studies were carried out in precision cut lung slices (PCLS) from PH patients. Knockdown of TYKRIL in PCLS decreased the vascular remodeling (n=5). The number of PCNA positive cells in the vessels were decreased and number of TUNEL positive cells in the vessels were increased in LNA treated group compared to control. Expression of PDGFRβ, a key player in PH, was found to strongly correlate with TYKRIL expression in the patient samples (n=12) and TYKRIL knockdown decreased PDGFRβ expression (n=3). Importantly, TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ by binding to the N-terminal of p53 and interfering with p53-p300 interaction that subsequently regulates p53 nuclear translocation. CONCLUSION: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis