TAK-272 (imarikiren), a novel renin inhibitor, improves cardiac remodeling and mortality in a murine heart failure model

• Published in: PloS one Vol. 13; no. 8; p. e0202176
• Main Authors: Hara, Tomoya, Nishimura, Satoshi, Yamamoto, Toshihiro, Kajimoto, Yumiko, Kusumoto, Keiji, Kanagawa, Ray, Ikeda, Shota, Nishimoto, Tomoyuki
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.08.2018; Public Library of Science (PLoS)
• Subjects: Amides - pharmacology; Analysis; Angiotensin; Animals; Apoptosis; Attenuation; Benzimidazoles - pharmacology; Biology and Life Sciences; Biomarkers; Blood pressure; Brain; Brain natriuretic peptide; Calsequestrin; Cardiac output; Cardiomyocytes; Cardiovascular Agents - pharmacology; Cardiovascular disease; Care and treatment; Control; Development and progression; Disease Models, Animal; Dosage and administration; Dose-Response Relationship, Drug; Drug dosages; Enzymes; Female; Fumarates - pharmacology; Health aspects; Heart; Heart - diagnostic imaging; Heart - drug effects; Heart attacks; Heart diseases; Heart failure; Heart Failure - diagnostic imaging; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - mortality; Hypertension; Hypertrophy; Hypertrophy - drug therapy; Hypertrophy - metabolism; Hypertrophy - mortality; Inhibition; Inhibitors; Injury prevention; Lung Diseases - drug therapy; Lung Diseases - metabolism; Lung Diseases - mortality; Lungs; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines - pharmacology; Mortality; NAD(P)H oxidase; Nitric oxide; Nitric-oxide synthase; NOS3 protein; Patient outcomes; Pharmaceutical industry; Piperidines - pharmacology; Protective Agents - pharmacology; Random Allocation; Renin; Renin - antagonists & inhibitors; Renin - blood; Renin inhibitors; Research and Analysis Methods; Risk factors; Rodents; Transgenic animals; Weight reduction; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0202176

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.