Hypoxia-induced Pulmonary Hypertension in Different Mouse Strains: Relation to Transcriptome

Area of Science:

• Genomics
• Cardiovascular Research
• Pulmonary Medicine

Background:

• Pulmonary arterial hypertension (PAH) has low disease penetrance with known mutations like BMPR2.
• Most PAH patients lack identifiable genetic mutations, indicating other susceptibility factors.
• Identifying novel genomic factors is crucial for understanding PAH pathogenesis.

Purpose of the Study:

• To identify genomic factors contributing to pulmonary arterial hypertension (PAH) pathogenesis.
• To investigate the mechanisms behind high right ventricular systolic pressure (RVSP) in the PL/J mouse strain under hypoxia.
• To explore potential therapeutic targets for hypoxia-induced PAH.

Main Methods:

• Exposed 32 mouse strains to chronic hypoxia.
• Performed RNAseq analysis on PL/J mouse lungs to identify upregulated microRNAs (miRNAs) and mRNAs.
• Analyzed T cell markers, C5a/C5AR1 expression, and RhoA/Rock pathway components.

Main Results:

• The PL/J strain exhibited extremely high RVSP with minimal lung remodeling under hypoxia.
• Hypoxia-induced miRNAs in PL/J mice targeted and downregulated T cell marker mRNAs.
• Increased C5a and C5AR1 expression, along with elevated Rho-associated protein kinase (Rock) 2 mRNA, were observed.
• Inhibition of Rock2 partially ameliorated elevated RVSP, and miR-150-5p was identified as a potential Rock2 regulator.

Conclusions:

• Two pathways contribute to hypoxia-induced PAH with high RVSP: aberrant T cell expression via miRNAs and increased C5a/C5AR1.
• The PL/J mouse model is valuable for studying mechanisms of RVSP elevation in hypoxia-induced PAH.
• Further research into these pathways may reveal new therapeutic strategies for PAH.