Cargando…
TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model
The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren),...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084973/ https://www.ncbi.nlm.nih.gov/pubmed/30092100 http://dx.doi.org/10.1371/journal.pone.0202176 |
_version_ | 1783346261876801536 |
---|---|
author | Hara, Tomoya Nishimura, Satoshi Yamamoto, Toshihiro Kajimoto, Yumiko Kusumoto, Keiji Kanagawa, Ray Ikeda, Shota Nishimoto, Tomoyuki |
author_facet | Hara, Tomoya Nishimura, Satoshi Yamamoto, Toshihiro Kajimoto, Yumiko Kusumoto, Keiji Kanagawa, Ray Ikeda, Shota Nishimoto, Tomoyuki |
author_sort | Hara, Tomoya |
collection | PubMed |
description | The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure. |
format | Online Article Text |
id | pubmed-6084973 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-60849732018-08-18 TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model Hara, Tomoya Nishimura, Satoshi Yamamoto, Toshihiro Kajimoto, Yumiko Kusumoto, Keiji Kanagawa, Ray Ikeda, Shota Nishimoto, Tomoyuki PLoS One Research Article The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure. Public Library of Science 2018-08-09 /pmc/articles/PMC6084973/ /pubmed/30092100 http://dx.doi.org/10.1371/journal.pone.0202176 Text en © 2018 Hara et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hara, Tomoya Nishimura, Satoshi Yamamoto, Toshihiro Kajimoto, Yumiko Kusumoto, Keiji Kanagawa, Ray Ikeda, Shota Nishimoto, Tomoyuki TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title | TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title_full | TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title_fullStr | TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title_full_unstemmed | TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title_short | TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
title_sort | tak-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084973/ https://www.ncbi.nlm.nih.gov/pubmed/30092100 http://dx.doi.org/10.1371/journal.pone.0202176 |
work_keys_str_mv | AT haratomoya tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT nishimurasatoshi tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT yamamototoshihiro tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT kajimotoyumiko tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT kusumotokeiji tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT kanagawaray tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT ikedashota tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel AT nishimototomoyuki tak272imarikirenanovelrenininhibitorimprovescardiacremodelingandmortalityinamurineheartfailuremodel |