Development of the molecular basis of novel therapeutic strategy for connective tissue disease-associated pulmonary hypertension

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461469
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: The University of Tokyo
• Principal Investigator: Yoshikawa Noritada 東京大学, 医科学研究所, 助教 (70396878)
• Co-Investigator(Renkei-kenkyūsha): Tanaka Hirotoshi 東京大学, 医科学研究所, 教授 (00171794) ; Shimizu Noriaki 東京大学, 医科学研究所, 特任研究員 (30396890) ; Sano Motoaki 慶應義塾大学, 医学部, 准教授 (30265798)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 膠原病 / 肺高血圧症 / 右心肥大 / 右心不全 / 心臓リモデリング / HEXIM1 / P-TEFb / HIF-1

Outline of Final Research Achievements

To develop novel therapeutic strategies for connective tissue disease (CTD)-associated pulmonary hypertension (PH), we hypothesized that direct interruption of fatal right ventricular hypertrophy (RVH)/RV remodeling improves their prognosis.
We investigated that overexpression of HEXIM1, which suppresses positive transcription elongation factor b-dependent transcription, prevents cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice (HEXcTg) ameliorates RVH in hypoxia-induced PH model. Moreover, we revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of hypoxia inducible factor 1α (HIF-1α) protein and its target genes in cardiomyocytes, and that HEXcTg repressed RV myocardial angiogenesis in hypoxia-induced PH model. We further investigated that HEXcTg could prevent RVH of bleomycin-induced PH/RVH model. Thus, HEXIM1 would be a molecular target for mitigating CTD-associated PH and RVH/RV remodeling.

Free Research Field

医歯薬学、内科系臨床医学・膠原病学、内分泌・代謝学、分子生物学