Development of a treatment for pulmonary arterial hypertension focusing on inflammatory endothelial dysfunction
Project/Area Number |
17K16033
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Cardiovascular medicine
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Research Institution | National Cardiovascular Center Research Institute |
Principal Investigator |
Inagaki Tadakatsu 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (20638366)
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Research Collaborator |
Masaki Takeshi
Mori Hiroyoshi
Fukushima Yasue
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Project Period (FY) |
2017-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | 肺動脈性肺高血圧症 / 肺血管リモデリング / 右心不全 / Interleukin-6 / 炎症 / 肺高血圧症 / 血管内皮機能障害 |
Outline of Final Research Achievements |
In this study, we used the severe PAH model (SuHx) to test the hypothesis that the onset of PAH and right heart failure involve inflammatory endothelial dysfunction in the lung and coronary blood vessels. In SuHx rats, Endothelium-dependent vasodilator responses were significantly attenuated in the middle and small arteries in the right coronary artery of SuHx rats. Endothelin receptor antagonist treatment recovered the endothelium-dependent vasodilator responses, improved the inflammatory state of the right ventricle and restored cardiac function. We also created IL-6 knockout (KO) rats using CRISPR/Cas9 genome editing. IL-6KO rats showed significant resistance to PAH. These results suggests that endothelial dysfunction of coronary arteries is involved in the onset of right heart failure, and that inhibition of inflammatory signals may be a promising new treatment for refractory PAH.
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Academic Significance and Societal Importance of the Research Achievements |
本研究では肺高血圧症における肺血管リモデリングおよび右冠動脈の異常収縮には炎症を背景とする血管内皮機能障害が関与するかについて、肺高血圧症における炎症性シグナルの分子機序から明らかにすることを目的とし、既存の治療薬に適応しない重症疾患患者に対する新たな治療法の確立を目指すものであった。本研究により、IL-6阻害がこれまでの既存の薬剤に適応しない重症肺高血圧患者に対して右心不全の予防や予後改善にまで発展する可能性が期待された。
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Report
(3 results)
Research Products
(22 results)
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[Journal Article] Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice.2018
Author(s)
Takeshita H, Yamamoto K, Nozato S, Takeda M, Fukada SI, Inagaki T, Tsuchimochi H, Shirai M, Nozato Y, Fujimoto T, Imaizumi Y, Yokoyama S, Nagasawa M, Hamano G, Hongyo K, Kawai T, Hanasaki-Yamamoto H, Takeda S, Takahashi T, Akasaka H, Itoh N, Takami Y, Takeya Y, Sugimoto K, Nakagami H, Rakugi H.
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Journal Title
J Cachexia Sarcopenia Muscle.
Volume: 9
Issue: 5
Pages: 975-986
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] 2.Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice.2017
Author(s)
Takeshita H, Yamamoto K, Nozato S, Inagaki T, Tsuchimochi H, Shirai M, Yamamoto R, Imaizumi Y, Hongyo K, Yokoyama S, Takeda M, Oguro R, Takami Y, Itoh N, Takeya Y, Sugimoto K, Fukada SI, Rakugi H.
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Journal Title
Scientific reports
Volume: 7
Issue: 1
Pages: 42323-42323
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model.2017
Author(s)
Pearson JT, Yoshimoto M, Chen YC, Sultani R, Edgley AJ, Nakaoka H, Nishida M, Umetani K, Waddingham MT, Jin HL, Zhang Y, Kelly DJ, Schwenke DO, Inagaki T, Tsuchimochi H, Komuro I, Yamashita S, Shirai M.
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Journal Title
Sci Rep
Volume: Dec 22;7(1)
Issue: 1
Pages: 18108-18108
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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