Non-Invasive Approach for Evaluation of Pulmonary Hypertension Using Extracellular Vesicle-Associated Small Non-Coding RNA.

Lipps Lipps,Rohde Rohde,Kriechbaum Kriechbaum,Troidl Troidl,Figueiredo Figueiredo,Mayer Mayer,Northe Northe,Krämer-Albers Krämer-Albers,Keller Keller,Brahmer Brahmer,Hamm Hamm,Wiedenroth Wiedenroth,Dörr Dörr,Liebetrau Liebetrau,Nef Nef

doi:10.3390/biom9110666

Abstract

Extracellular vesicles are released by numerous cell types of the human body under physiological but also under pathophysiological conditions. They are important for cell–cell communication and carry specific signatures of peptides and RNAs. In this study, we aimed to determine whether extracellular vesicles isolated from patients with pulmonary hypertension show a disease specific signature of small non-coding RNAs and thus have the potential to serve as diagnostic and prognostic biomarkers. Extracellular vesicles were isolated from the serum of 23 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and 23 controls using two individual methods: a column-based method or by precipitation. Extracellular vesicle- associated RNAs were analyzed by next-generation sequencing applying molecular barcoding, and differentially expressed small non-coding RNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). We identified 18 microRNAs and 21 P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) or piRNA clusters that were differentially expressed in CTEPH patients compared with controls. Bioinformatic analysis predicted a contribution of these piRNAs to the progression of cardiac and vascular remodeling. Expression levels of DQ593039 correlated with clinically meaningful parameters such as mean pulmonary arterial pressure, pulmonary vascular resistance, right ventricular systolic pressure, and levels of N-terminal pro-brain natriuretic peptide. Thus, we identified the extracellular vesicle- derived piRNA, DQ593039, as a potential biomarker for pulmonary hypertension and right heart disease.

Highlights

Pulmonary hypertension (PH) is characterized by high blood pressure in pulmonary arteries, making the right side of the heart work harder
Samples were used from 23 randomly selected Chronic thromboembolic pulmonary hypertension (CTEPH) patients with mean pulmonary arterial pressure (mPAP) ≥30 mmHg that were enrolled in an ongoing biomarker registry at the Kerckhoff Heart and Thorax Center
The size of the extracellular vesicles (EVs) was measured by nanoparticle tracking analysis

Summary

Introduction

Pulmonary hypertension (PH) is characterized by high blood pressure in pulmonary arteries, making the right side of the heart work harder. Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary. Biomolecules 2019, 9, 666 vascular disease that is classified as group IV in the current clinical classification of PH [1]. It is characterized by persistent thromboembolic obstruction of pulmonary arteries and progressive vascular remodeling that leads to an increased invasively measured mean pulmonary arterial pressure (mPAP). Equal to or higher than 25 mmHg. The increase in pulmonary vascular resistance results in progressive vascular remodeling and right heart failure, limiting the life expectancy of the patients [2]. An early and accurate diagnosis of the underlying condition is required to apply the appropriate treatment strategy

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