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Transcriptomic analysis of the left and right ventricles in a rat model of pulmonary hypertension

ABSTRACT: Pulmonary hypertension (PH) encompasses a diverse spectrum of disorders characterized by elevated pulmonary arterial pressure presenting substantial morbidity and mortality challenges. Despite significant advancements in understanding its underlying pathophysiology therapeutic options remain limited particularly in cases where patients exhibit elevated pulmonary pressures despite maintaining a preserved left ventricular ejection fraction. The traditional focus on right ventricular (RV) function in PH has led to the underestimation of the impact on the left ventricle (LV) due to the absence of high-resolution modalities capable of monitoring the electromechanical coupling in both ventricles. We present here the results of an integrated histology and transcriptome analysis used to improve our understanding of the pathophysiology of pulmonary hypertension and identify the different molecular responses due to MCT-induced PH.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE266139 | GEO | 2025/07/16

REPOSITORIES: GEO

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Project description:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.

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Transcriptomic analysis of the left and right ventricles in a rat model of pulmonary hypertension

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