Transcriptional changes in right ventricular tissues are enriched in the outflow tract compared with the apex during chronic pulmonary embolism in rats

Abstract

Moderate to severe pulmonary embolism (PE) can cause pulmonary arterial hypertension and right ventricular (RV) heart damage. Previous studies from our laboratory indicate that the basal outflow tract of the RV is injured and has acute inflammation followed by tissue remodeling while the apex appears normal. The present studies examine transcription responses to chronic PE in RV apex and outflow tracts using DNA microarrays to identify transcription responses by region. Changes predominated in the RV outflow tract (8,575 genes showed >/=1.5-fold expression change). Gene ontology and KEGG analyses indicated a significant decrease in genes involved in cellular respiration and energy metabolism and increases in inflammatory cell adhesion molecules and extracellular matrix proteins. Signal pathways for wound healing such as fibroblast growth factor, collagen synthesis, and CCN proteins (named for the first three members of the family: cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene) were strongly upregulated. In comparison, few genes (422) showed significant change in the RV apex tissue. Apex-selective genes included two genes affecting metabolism and a stretch-sensitive transcription factor (ankyrin repeat domain 1). We conclude that the RV outflow tract is subject to strong proinflammatory and profibrotic remodeling transcriptional responses in chronic PE. Severe loss of genes involved in cellular respiration is consistent with previous histology indicating a shift in cell types present within the outflow tract tissue away from highly energy-dependant cardiomyocytes to less metabolically active cells during remodeling. The apex region of the RV had few compensating adaptations.

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

“…The primary insult with PE comes from macrovessel occlusion, whereas ARDS results from microvessel occlusion with widespread but heterogeneous alveolar consolidation and elements of acute hypoxic pulmonary vasoconstriction. Both conditions shift the pulmonary vasoconstrictor-dilator balance toward an increase in afterload and result in chemokine and cytokine release, recruitment of inflammatory cells, and production of reactive oxygen species (95)(96)(97)(98)(99)(100)(101). LV diastolic dysfunction (i.e., stiffness) may arise after acute PE and persist despite PH resolution (102-104) but likely is not a main contributor to symptoms.…”

Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial

“…25 2. Natriuretic peptide precursor B (gene ID 4879), a gene that we have previously shown by microarray analysis to be specifically upregulated in the RV outflow tract with PE 26 and 3. microRNA 134, found to be a good diagnostic biomarker for PE that is specifically increased in the plasma of humans 27 . The hypothesis is that there will be a more complete and rapid reduction with NO treatment.…”

Impact of a Mechanical Massage on Gene Expression Profile and Lipid Mobilization in Female Gluteofemoral Adipose Tissue

“…[18,28]. Tissue mechanical stretch has been studied in cardiomyocytes [29] and skeletal muscle especially in the context of exercise [30], but studies on adipose tissue are scarce. Up to now, no largescale study has focused on the effects of mechanical challenges on human GAT.…”