Research Projects -
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心血管メカノセンサーTRPV2の低酸素誘発性肺高血圧症への関与解明と治療法開発
Grant number：21K08108 2021.04 - 2024.03
日本学術振興会 科学研究費助成事業 基盤研究(C) 基盤研究(C)
中村 一文, 鵜殿 平一郎, 片野坂 友紀, 赤木 達
Grant amount：\4030000 （ Direct expense: \3100000 、 Indirect expense：\930000 ）
持続的な低酸素症は肺血管収縮を引き起こし、肺血管リモデリングや肺高血圧症（PH）の原因となる。しかし、血管収縮が血管リモデリングにつながる正確なメカニズムはまだ解明されていない。TRPV2は、Ca2+透過性カチオンチャネルであり、血管平滑筋の膜伸張に応答するメカノセンサーである。本研究の目的は、低酸素誘発性PHの発症における血管平滑筋のTRPV2の役割を明らかにすることである。血管平滑筋特異的 TRPV2 欠損マウス（smTRPV2-/-）を作製したところ、定量的PCRにより、smTRPV2-/-マウスから分離した肺動脈平滑筋細胞においてTRPV2が欠損していることが明らかとなった。フロックスコントロール（smTRPV2flox/flox）マウスとsmTRPV2-/-マウスを低酸素および正常酸素に5週間曝露したところ、低酸素によるPHはsmTRPV2-/-マウスではsmTRPV2flox/floxマウスと比較して有意に改善された。低酸素による肺動脈の完全筋肉化の割合は、smTRPV2-/-マウスはsmTRPV2flox/floxマウスに比べ有意に低かった。MTTアッセイにより、低酸素はsmTRPV2flox/floxマウスおよびsmTRPV2-/-マウスの両方の培養肺動脈平滑筋細胞の増殖を促進することが明らかになった。しかし、smTRPV2-/-PASMCsの低酸素による増殖率は、smTRPV2 flox/flox -肺動脈平滑筋細胞のそれよりも有意に小さかった。上記よりTRPV2は、肺動脈平滑筋細胞の不適切な増加とともに、低酸素によるPHの発症に重要な役割を担っていることがわかった（本結果を2021年、2022年日本循環器学術集会において発表した）。
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Energy metabolism of idiopathic pulmonary arterial hypertension
Grant number：20K08424 2020.04 - 2023.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Akagi Satoshi
Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）
Pulmonary artery smooth muscle cells (PASMCs) of pulmonary arterial hypertension (PAH) have similar metabolic characteristics of cancer cells. We investigated metabolic state of PAH-PASMCs under normoxia and hypoxia. Glycolytic switch was occurred under normoxia and mitochondrial respiration was preserved under hypoxia in PAH-PASMCs, which resulted in increase of ATP production in PAH-PASMCs under hypoxia. These characteristics of energy metabolism in PAH-PASMCs under normoxia and hypoxia might be involved in the pathogenesis of PAH.
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Uremic toxin and the development of heart failure
Grant number：19K08558 2019.04 - 2022.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Ito Hiroshi
Grant amount：\4290000 （ Direct expense: \3300000 、 Indirect expense：\990000 ）
The number of patients with heart failure is increasing with aging population in Japan. Cardio-renal interaction plays an important role in the pathophysiology of heart failure. Recent studies showed that chronic kidney disease (CKD) is associate with an increased risk of cardiovascular events. However, mechanisms underlying between CKD and cardiovascular events remains unclear. In this study, indoxyl sulfate, an uremic toxin, was measured in patients with heart failure and its association with prognosis was evaluated in a multicenter cohort. Indoxyl sulfate levels in patients with heart failure were significantly associated with the incidence of cardiovascular events including cardiovascular death, stroke, acute myocardial infarction in patients with heart failure. These results suggest that indoxyl sulfate could be a therapeutic target in patients with heart failure and CKD.
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Development of new treatments with RAGE-aptamer-incorporated nanoparticles for pulmonary arterial hypertension
Grant number：18K08037 2018.04 - 2021.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C) Grant-in-Aid for Scientific Research (C)
Nakamura Kazufumi
Grant amount：\4420000 （ Direct expense: \3400000 、 Indirect expense：\1020000 ）
1.Inhibitory effects of RAGE-aptamer on development of monocrotaline-induced pulmonary arterial hypertension in rats.: Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for pulmonary arterial hypertension (PAH).
2.Inhibitory effects of RAGE-aptamer on proliferation of pulmonary artery smooth muscle cells (PASMCs) from patients with PAH: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling using RAGE aptamer inhibited the inappropriate increase of PAH-PASMCs. -
Grant number：17K09498 2017.04 - 2020.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C) Grant-in-Aid for Scientific Research (C)
Akagi Satoshi
Grant amount：\4550000 （ Direct expense: \3500000 、 Indirect expense：\1050000 ）
Idiopathic pulmonary arterial hypertension (IPAH) has characteristics with remarkable elevation of pulmonary artery pressure and dysfunction of right ventricular. Drugs for IPAH targets pulmonary arteries but did not directly target right ventricle. In this study we successfully created iPS cells from fibroblast obtained from patient with IPAH. Next, we successfully induced cardiomyocyte. Cardiomyocyte from IPAH patient had characteristic that energy metabolism depends on glycolysis under both normoxia and hypoxia.
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Development of new treatments with suppression of RAGE signal for pulmonary hypertension
Grant number：15K09158 2015.04 - 2018.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C) Grant-in-Aid for Scientific Research (C)
NAKAMURA Kazufumi
Grant amount：\4940000 （ Direct expense: \3800000 、 Indirect expense：\1140000 ）
1.After a single administration, imatinib or beraprost-nanoparticles significantly decreased right ventricular pressure and right ventricular hypertrophy in rat models of pulmonary arterial hypertension (PAH).
2.Pulmonary artery smooth muscle cells of PAH (PAH-PASMCs) were hyperplastic. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth in PAH-PASMCs. -
New therapy for pulmonary hypertension using prostaglandin I2 incorporated nanoparticles
Grant number：26860563 2014.04 - 2016.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B) Grant-in-Aid for Young Scientists (B)
AKAGI Satoshi
Grant amount：\3770000 （ Direct expense: \2900000 、 Indirect expense：\870000 ）
We prepare the beraprost incorporated nanoparticles (BPS-NPs) and investigated the effects on pulmonary hypertension in Sugen-hypoxia and monocrotaline rat models of pulmonary arterial hypertension (PAH). We examined the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and pulmonary vascular remodeling 2 weeks after the intratracheal administration of PBS, FITC incorporated nanoparticle (FITC-NPs) and BPS-NPs. BPS-NPs significantly decreased RVSP, RVH and pulmonary vascular remodeling compared with PBS and FITC-NPs in Sugen-hypoxia and monocrotaline rat models. Furthermore, BPS-NPs significantly improved survival rate compared with PBS and FITC-NPs in monocrotaline rat models.