Program

PO3-3-35

Identification of a Novel Gene that is involved in Pulmonary Arterial Hypertension Development

[Speaker] Gusti Rizky Teguh Ryanto:1
[Co-author] Koji Ikeda:2, Kazuya Miyagawa:2, Keiko Yagi:2, Yoko Suzuki:1,2, Ken-Ichi Hiirata:1, Noriaki Emoto:1,2
1:Cardiovascular Medicine, Internal Medicine, Kobe University Graduate School of Medicine, Japan, 2:Clinical Pharmacy, Kobe Pharmaceutical University, Japan

Background: Pulmonary arterial hypertension (PAH), a fatal disease due to right ventricle dysfunction, is pathologically signified by pulmonary arterial remodeling, especially in the microvessels. Endothelial cell (EC) dysfunction has been known to be one of the main causes of the vascular remodeling; however, the molecular mechanisms underlying pulmonary arterial remodeling remains poorly understood.

Methods: To identify genes that are involved in PAH development, we specified on genes regulating lung microvessel homeostasis and thus performed DNA microarray analysis using RNAs isolated from human ECs from various vascular beds, including lung microvessels, and various human organs, including the lung. After candidate gene was found, we confirmed the modulation of its expression in human pulmonary artery ECs (hPAECs) exposed to hypoxia. Next, we overexpressed the candidate gene in hPAEC using retrovirus and analyzed its functions via angiogenesis assays (tube formation, migration and apoptosis). We then generated mice with targeted candidate gene activation in ECs (via VE-cadherin promotor utilization) and exposed them to normoxia or hypoxia (10% O¬2 for 3 weeks) to evaluate the PAH phenotypes.

Results: Microarray analysis revealed INHBA as a gene that is highly and preferentially expressed in the human lung microvasculature ECs. INHBA overexpression in hPAECs caused a dramatic reduction of EC angiogenic capacities (reduced EC tube formation and migration capability with increased apoptosis). Transgenic mice overexpressing INHBA in ECs (VEcad-INHBA-Tg) showed significantly higher pulmonary arterial pressure and right ventricular hypertrophy with evidences of arterial remodeling. After 3 weeks of chronic hypoxia, PAH phenotypes were exacerbated in TG mice compared to control wild-type.

Conclusion: Our data suggest that INHBA is important in regulating PAH development, and thus INHBA could be a novel therapeutic target in PAH treatment.
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