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

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.

An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis

“…Consistently, the highest number of shared differentially expressed SMC genes was found between our microfluidic PAH models (94 genes), between the two-hit ECFC PAH model and IPAH PASMCs 25 (86 genes) and between the two-hit HPAEC PAH model and IPAH PASMCs (76 genes) (Fig. 6c and Supplementary Data 10 ).…”

“…Consistently, the highest number of shared differentially expressed SMC genes was found between our microfluidic PAH models (94 genes), between the two-hit ECFC PAH model and IPAH PASMCs 25 (86 genes) and between the two-hit HPAEC 22 (database named here IPAH PASMCs); PAECs isolated from IPAH lung transplants 23 (named here IPAH PAEC). Other comparative gene sets included genes with known PAH-associations 24 (here named "known PAH2") and the DisGENET public database https://www.disgenet.org/search, where following gene sets were obtained: DisGENET PAH (https://www.disgenet.org/browser/0/1/0/ C2973725/), (here named "known PAH1"); DisGENET IPAH (https://www.disgenet.org/browser/0/1/0/C3203102/) (here named "known IPAH1").…”

Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia

“…Moreover, it is important to highlight that a recent study in rats exposed to a chronic hypobaric hypoxia indicate that the RV differed from the left ventricle both in immune cells and expression of certain genes; therefore, this suggests that the two ventricles differ in aspects of pathophysiology and in potential therapeutic targets for RV dysfunction [ 71 ]. While these studies are not fully comparable to the hypoxic conditions in the current study, they provide new avenues to surmise hypothetical similar changes under CIH and future targets of study.…”

Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

“… Antifibrotic therapies that are effective in the LV (pirfenidone and eplerenone) do not reverse fibrosis in the RV ( 57 , 72 ). Inflammation RV has more macrophages and dendritic cells at baseline compared with the LV ( 95 ). Estrogen signaling In the dysfunctional RV, the beneficial effects of estrogen are predominately mediated by ER-α ( 98 ), but in LV pressure overload, stimulation of ER-β normalizes LV ejection fraction ( 106 ).…”

“…There are inherent differences in the inflammatory cell populations in the LV and RV, suggesting inflammation may have different effects on each ventricle. Mouse studies show the RV has a 4-fold increase in macrophages and dendritic cells at baseline compared with the LV ( 95 ). Perhaps pathological inflammation may disproportionately affect the RV, and therefore anti-inflammatory therapies may preferentially augment RV function.…”