Transcriptomic profiles reveal differences between the right and left ventricle in normoxia and hypoxia.

Matthew W Gorr,Amy M Chinn,Krishna Sriram,Abinaya Muthusamy,Paul A Insel

doi:10.14814/phy2.14344

Matthew W Gorr, Amy M Chinn + Show 3 more

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https://doi.org/10.14814/phy2.14344

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Abstract

Chronic hypoxia from diseases in the lung, such as pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease, can increase pulmonary vascular resistance, resulting in hypertrophy and dysfunction of the right ventricle (RV). In order to obtain insight into RV biology and perhaps uncover potentially novel therapeutic approaches for RV dysfunction, we performed RNA‐sequencing (RNA‐seq) of RV and LV tissue from rats in normal ambient conditions or subjected to hypoxia (10% O2) for 2 weeks. Gene ontology and pathway analysis of the RV and LV revealed multiple transcriptomic differences, in particular increased expression in the RV of genes related to immune function in both normoxia and hypoxia. Immune cell profiling by flow cytometry of cardiac digests revealed that in both conditions, the RV had a larger percentage than the LV of double‐positive CD45+/CD11b/c+ cells (which are predominantly macrophages and dendritic cells). Analysis of gene expression changes under hypoxic conditions identified multiple pathways that may contribute to hypoxia‐induced changes in the RV, including increased expression of genes related to cell mitosis/proliferation and decreased expression of genes related to metabolic processes. Together, the findings indicate that the RV differs from the LV with respect to content of immune cells and expression of certain genes, thus suggesting the two ventricles differ in aspects of pathophysiology and in potential therapeutic targets for RV dysfunction.

Highlights

Chronic hypoxia in diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, and pulmonary fibrosis can lead to increased pulmonary vascular resistance and result in increased afterload to the right ventricle (RV) (Lettieri, Nathan, Barnett, Ahmad, & Shorr, 2006; Ryan & Archer, 2014; Terzano et al, 2010)
We found an increase in the CD45+/CD11b/c+ population in the RV compared to the left ventricle (LV) of rats exposed to normoxia or hypoxia ((p < .05 via two-way ANOVA) but without changes induced by hypoxia. (Figure 5b–d)
These studies revealed that exposure of rats to 2 weeks of hypoxia induces RV hypertrophy and numerous changes in gene expression in both the RV and LV

Summary

| INTRODUCTION

Chronic hypoxia in diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, and pulmonary fibrosis can lead to increased pulmonary vascular resistance and result in increased afterload to the right ventricle (RV) (Lettieri, Nathan, Barnett, Ahmad, & Shorr, 2006; Ryan & Archer, 2014; Terzano et al, 2010). | 2 of 12 generally considered to be identical to that of the LV, RV failure has a poorer prognosis and response to therapy compared to LV disease, due in part to factors independent of the increase in pulmonary arterial (PA) pressure (Ghio et al, 2001) These unexplained factors are manifested as disproportional levels of fibrosis, alterations in metabolism, and RV ischemia (Ryan & Archer, 2014). Transcriptomic analysis using RNA sequencing (RNA-seq) is an unbiased approach to define gene expression and may offer a means to study the pathobiology of RV disease and uncover new mechanisms that might help identify novel RV-specific therapies. Animal models, such as chronic hypoxia, can mimic the RV remodeling in humans in response to increased PA pressure. The RV and LV differ in their gene expression profiles and unexpectedly, in their expression of certain cell types, in particular cells involved in immune function

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Findings

| DISCUSSION