Role of IPAS/HIF-3alpha-mediated signals in the pathophysiology of pulmonary hypertension associated with connective tissue disease

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461456
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Makino Yuichi 旭川医科大学, 医学部, 准教授 (90345033)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 一塩基多型 / エンドセリン1 / 低酸素 / 膠原病 / 肺高血圧症 / HIF

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a poor prognostic complication of connective tissue disease (CTD). Increased expression of endothelin-1 (ET-1) is of particular interest for its pathogenic role in PAH. We previously identified non-synonymous single nucleotide polymorphisms (SNPs) of HIF3A gene in the patients with systemic sclerosis (SSc) associated with PAH and demonstrated that ET-1 mRNA is induced by overexpression of HIF-3α carrying the SNPs (SNP-HIF3α) even under normoxic condition. In this study, we aim to further investigate the pathophysiological roles of SNP-HIF3α in ET-1 regulation with respect to PAH. We found SSc-PAH related SNP-HIF3α is a potent transcriptional activator of ET-1 gene. Upregulated ET-1 by SNP-HIF3αcaused enhancement of proliferation and migration of pulmonary artery smooth muscle cells. In conclusion, SNP-HIF3α might paly a role in dysregulation of pulmonary arterial remodeling and contribute to pathogenesis of PAH in SSc.

Free Research Field

内科学、膠原病学