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

Abstract

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.

Fig 1. Survival rates of calsequestrin transgenic (CSQ-tg) mice treated with vehicle or TAK-272.

Vehicle, TAK-272 30, 100, or 300 mg/kg were orally treated once daily to CSQ-tg mice. Each treatment group was comprised of 20 animals. The number of animals which were euthanized or found dead is the following; Vehicle (E: 16, F: 4), TAK-272 30 mg/kg (E: 17, F: 1), 100 mg/kg (E: 9, F: 6), 300 mg/kg (E: 2, F: 6) (E: euthanasia, F: found dead). **P < 0.01 vs. vehicle by Kaplan–Meier survival analysis with a log-rank test followed by the Bonferroni correction.

Fig 2. Effects of TAK-272 on the plasma renin activity (PRA) and blood pressure (BP).

The PRA (A) and systolic BP (SBP) (B) of wild-type (WT) and calsequestrin transgenic (CSQ-tg) mice at 24 h after 7 days of treatment with vehicle or TAK-272 (300 mg/kg) are indicated. The number of deaths in each group during the PRA study was as follows: 0, 1, and 0 in WT, CSQ-tg + vehicle, and 300 mg/kg TAK-272 groups, respectively. No death was observed in the BP study groups. Data are expressed as the mean + S.D. ^##P < 0.01 vs. WT by Student's t-test, *P < 0.05 vs. CSQ-tg + vehicle by Aspin-Welch's t-test.

Fig 3. Effects of TAK-272 on the expression of renin angiotensin system (RAS)-related genes and cardiac injury markers.

The left ventricular NADPH oxidase 4 (Nox4), nitric oxide synthase 3 (Nos3), transforming growth factor-β1 (TGF-β1), and collagen type I α1 (Col1α1) expression (A) and plasma cardiac troponin I (cTnI) levels (B) in wild-type (WT) and calsequestrin transgenic (CSQ-tg) mice after 16–17 days of treatment with vehicle or TAK-272 (300 mg/kg) are indicated. The number of deaths in each group during the study period was as follows: 0, 5, and 1 in WT, CSQ-tg + vehicle, and 300 mg/kg TAK-272 groups, respectively. Data are expressed as the mean + S.D. ^##P < 0.01 vs. WT by Aspin-Welch's t-test or Student's t-test, *P < 0.05 vs. CSQ-tg + vehicle by Student's t-test.

Fig 4. Comparison of the efficacy of TAK-272 and aliskiren with respect to plasma renin activity (PRA) inhibition.

The PRA in calsequestrin transgenic (CSQ-tg) mice after single oral administration of vehicle, TAK-272 (300 mg/kg), or aliskiren (300 mg/kg) is indicated. Data are expressed as the mean + S.D. **P < 0.01 vs. vehicle by Dunnett's test followed by the Bonferroni correction.