Differential Gene Expression in the Lungs of Rats with Experimental Chronic Thromboembolic Pulmonary Hypertension

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Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) remains a severe disease with low survival rates in inoperable patients, despite advances in treatment. The molecular mechanisms underlying CTEPH pathogenesis are not fully understood, necessitating further research to identify new therapeutic targets. Although numerous animal models of CTEPH have been developed, demonstrating their clinical relevance requires establishing molecular bioequivalence with human pathophysiological processes, particularly through matching gene expression profiles. To analyze differential gene expression in rat lung tissues following CTEPH modeling using alginate microsphere administration and to assess the applicability of this model for developing and studying new therapeutic strategies for CTEPH. CTEPH was modeled in Wistar rats via repeated intravenous injections of biodegradable alginate microspheres. The transcriptional profile of lung tissue samples collected from CTEPH rats at 2 weeks, 6 weeks, and control rats was analyzed using high-throughput RNA sequencing. Differentially expressed genes (DEGs) were identified using DESeq2. Gene expression changes were validated by reverse transcription PCR (RT-PCR). Transcriptomic analysis revealed that CTEPH modeling at 2 weeks upregulated genes associated with inflammation, whereas at 6 weeks, downregulation of extracellular matrix-related genes was observed. Transcription factor analysis showed predominant regulation of DEG promoters by C2H2 zinc finger proteins Zfp278 and KIF5, suggesting their involvement in the cellular response during CTEPH development. RT-PCR validation of Cav1, Eng, vWF, and Gja5 expression in a larger set of lung tissue samples confirmed the dynamic changes detected in the transcriptomic analysis. This study identified dynamic transcriptional changes during CTEPH development in rats, including dysregulation of extracellular matrix, inflammation, and endothelial dysfunction-related genes, consistent with current understanding of CTEPH pathogenesis. The findings demonstrate that the developed rat model exhibits transcriptional profile alterations comparable to those observed in human CTEPH, supporting its relevance for preclinical research.

About the authors

N. S Vachrushev

Almazov National Medical Research Centre

Email: drabrikos@gmail.com
Saint-Petersburg, Russia

L. A Shilenko

Almazov National Medical Research Centre

Saint-Petersburg, Russia

A. A Karpov

Almazov National Medical Research Centre; Saint Petersburg State Chemical and Pharmaceutical University

Saint-Petersburg, Russia; Saint-Petersburg, Russia

D. Y Ivkin

Saint Petersburg State Chemical and Pharmaceutical University

Saint-Petersburg, Russia

M. M Galagudza

Almazov National Medical Research Centre

Saint-Petersburg, Russia

A. A Kostareva

Almazov National Medical Research Centre

Saint-Petersburg, Russia

O. V Kalinina

Almazov National Medical Research Centre; Saint-Petersburg Pasteur Institute

Saint-Petersburg, Russia

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