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Abstract <p>Chronic thromboembolic pulmonary hypertension (CTEPH) remainsa severe disease with low survival rates in inoperable patients,despite advances in treatment. The molecular mechanisms underlyingthe pathogenesis of CTEPH are not fully understood, necessitatingfurther research to identify new therapeutic targets. Although numerousanimal models of CTEPH have been developed, demonstrating theirclinical relevance requires establishing molecular bioequivalencewith human pathophysiological processes, particularly through matchinggene expression profiles. The aim of this study was to analyze differentialgene expression in rat lung tissues following CTEPH modeling via alginatemicrosphere administration and to assess the applicability of thismodel for developing and investigating new therapeutic strategiesfor CTEPH. CTEPH was modeled in Wistar rats via repeated intravenousinjections of biodegradable alginate microspheres. The transcriptionalprofile in lung tissue samples collected from CTEPH rats at weeks2 and 6, as well as from control rats, was analyzed using high-throughputRNA sequencing technology. Differentially expressed genes (DEGs)were identified via DESeq2. Gene expression changes were validatedby reverse transcription polymerase chain reaction (RT-PCR). Transcriptomicanalysis revealed that CTEPH modeling at week 2 upregulated the expressionof inflammation-related genes, whereas at week 6, it downregulatedthe expression of extracellular matrix-related genes. Transcriptionfactor analysis showed a predominant regulation of DEG promotersby Cys2-His2 zinc finger (C2H2 ZF) proteins Zfp278 and Klf5, suggestingtheir involvement in the cellular response during CTEPH development.RT-PCR analysis of <i>Cav1</i>, <i>Eng</i>, <i>vWF</i>,and <i>Gja5</i> gene expression ina larger sample set of lung tissue confirmed its dynamics detectedin the transcriptomic analysis. Here, we revealed dynamic transcriptionalchanges during CTEPH development in rats, including the dysregulationof extracellular matrix-, inflammation-, and endothelial dysfunction-relatedgenes, consistent with the current understanding of CTEPH pathogenesis.The data obtained demonstrate the comparability of the developedrat model with the clinical course of CTEPH in humans at the transcriptionallevel, supporting its relevance for preclinical research.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月1日

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  • N. S. Vachrushev,
  • L. A. Shilenko,
  • A. A. Karpov,
  • D. Yu. Ivkin,
  • M. M. Galagudza,
  • A. A. Kostareva,
  • O. V. Kalinina

摘要

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) remainsa severe disease with low survival rates in inoperable patients,despite advances in treatment. The molecular mechanisms underlyingthe pathogenesis of CTEPH are not fully understood, necessitatingfurther research to identify new therapeutic targets. Although numerousanimal models of CTEPH have been developed, demonstrating theirclinical relevance requires establishing molecular bioequivalencewith human pathophysiological processes, particularly through matchinggene expression profiles. The aim of this study was to analyze differentialgene expression in rat lung tissues following CTEPH modeling via alginatemicrosphere administration and to assess the applicability of thismodel for developing and investigating new therapeutic strategiesfor CTEPH. CTEPH was modeled in Wistar rats via repeated intravenousinjections of biodegradable alginate microspheres. The transcriptionalprofile in lung tissue samples collected from CTEPH rats at weeks2 and 6, as well as from control rats, was analyzed using high-throughputRNA sequencing technology. Differentially expressed genes (DEGs)were identified via DESeq2. Gene expression changes were validatedby reverse transcription polymerase chain reaction (RT-PCR). Transcriptomicanalysis revealed that CTEPH modeling at week 2 upregulated the expressionof inflammation-related genes, whereas at week 6, it downregulatedthe expression of extracellular matrix-related genes. Transcriptionfactor analysis showed a predominant regulation of DEG promotersby Cys2-His2 zinc finger (C2H2 ZF) proteins Zfp278 and Klf5, suggestingtheir involvement in the cellular response during CTEPH development.RT-PCR analysis of Cav1, Eng, vWF,and Gja5 gene expression ina larger sample set of lung tissue confirmed its dynamics detectedin the transcriptomic analysis. Here, we revealed dynamic transcriptionalchanges during CTEPH development in rats, including the dysregulationof extracellular matrix-, inflammation-, and endothelial dysfunction-relatedgenes, consistent with the current understanding of CTEPH pathogenesis.The data obtained demonstrate the comparability of the developedrat model with the clinical course of CTEPH in humans at the transcriptionallevel, supporting its relevance for preclinical research.