Identification of a Novel Gene that is Critically Involved in the Development of Pulmonary Arterial Hypertension

Author : G. R. T. Ryanto, K. Ikeda, K. Miyagawa, K. Yagi, Y. Suzuki, K. Hiirata1, N. Emoto
Upload Date : 19-04-2018

Background Pulmonary arterial hypertension (PAH) is a disease causing elevated pulmonary artery pressure and consequent right heart failure. In PAH patients, pulmonary arteries are compromised, especially in microvessels, by a pathological process called vascular remodeling. One of the main causes of the vascular remodeling is endothelial cell (EC) dysfunction, but its underlying molecular mechanisms remain poorly understood. In this study, we aim to identify a novel gene that is critically involved in PAH development.

Methods We searched for genes highly and preferentially expressed in lung microvascular ECs through DNA microarray analysis using RNA samples from human ECs isolated from various vascular beds as well as RNAs from various human organs. Subsequently, expressional regulation of the target gene in human pulmonary artery ECs (hPAEC), lung microvascular ECs (hMVEC-L), and mouse lung ECs (MLEC) in response to hypoxia was analyzed. A role of the target gene on EC angiogenic functions was analyzed in hPAEC through gain-of-function study using retrovirus-mediated gene transfer. Finally, we generated mice with targeted activation of the gene in ECs to reveal its role in the PAH pathophysiology in vivo.

Results INHBA was found to be highly and preferentially expressed in the hMVEC-L through the DNA microarray analysis. INHBA mRNA expression was significantly reduced in hPAEC, hMVEC-L and MLEC in response to hypoxia, whereas INHBA overexpression in hPAECs caused a significant reduction in EC angiogenic capacities (reduced tube formation and migration capability with increased apoptosis). Targeted activation of INHBA in EC caused exacerbated PAH features such as higher pulmonary arterial pressure and right ventricular hypertrophy, accompanied by pathological evidences of arterial remodeling in mice.

Conclusion Our data revealed that INHBA is critically involved in PAH development and thus INHBA could be a novel therapeutic target in the treatment for PAH.

KEYWORDS : Pulmonary Arterial Hypertension, Angiogenesis, Endothelial Cells

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